835 results on '"Caffeine pharmacokinetics"'
Search Results
2. A comparative study of passive drug diffusion through human skin via intercellular and sweat duct route: effect of aging.
- Author
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Ranjan A, Duryodhan VS, and Patil ND
- Subjects
- Humans, Diffusion, Middle Aged, Adult, Caffeine pharmacokinetics, Caffeine administration & dosage, Caffeine chemistry, Sweat Glands metabolism, Models, Biological, Hydrocortisone pharmacokinetics, Hydrocortisone chemistry, Hydrocortisone administration & dosage, Benzoic Acid chemistry, Benzoic Acid pharmacokinetics, Aged, Pharmaceutical Preparations chemistry, Pharmaceutical Preparations metabolism, Pharmaceutical Preparations administration & dosage, Skin metabolism, Skin Absorption, Aging metabolism
- Abstract
A method of drug delivery that could provide control over medicine reaching the bloodstream for systemic circulation would be of immense importance. This work presents a comparative study of the temporal and spatial variation of drugs diffusing passively through two separate routes of human skin, namely intercellular (ICR) and sweat duct route (SDR). An analysis is carried out for two age groups (young < 40 years and old > 60 years of age). Governing equations based on Fick's law for mass transfer have been solved numerically using an in-house developed code. The code has been validated thoroughly with numerical and experimental work from the literature. Each skin route is modeled into three compartments sandwiched between the donor and receiver compartments. To understand the role of diffusion and partition coefficient on drug permeation, four drugs, namely hydrocortisone, trans-cinnamic acid, caffeine, and benzoic acid, are considered. The drug diffusion rate is found greater through ICR as compared to SDR. Further, the amount of drugs diffusing through both routes increases with age. Desirable drug characteristic is inferred to be a lower value of partition coefficient and a higher value of diffusion coefficient. This study could lead to real-time assessment of drugs reaching the bloodstream and beyond., (© 2024. Controlled Release Society.)
- Published
- 2024
- Full Text
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3. The Tissue-Specific Eco-Exposome: Differential Pharmaceutical Bioaccumulation and Disposition in Fish among Trophic Positions.
- Author
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Sims JL, Cole AR, Moran ZS, Mansfield CM, Possamai B, Rojo M, King RS, Matson CW, and Brooks BW
- Subjects
- Animals, Bioaccumulation, Tissue Distribution, Carbamazepine metabolism, Carbamazepine pharmacokinetics, Sucrose metabolism, Sucrose analogs & derivatives, Caffeine metabolism, Caffeine pharmacokinetics, Liver metabolism, Selective Serotonin Reuptake Inhibitors metabolism, Selective Serotonin Reuptake Inhibitors pharmacokinetics, Gills metabolism, Environmental Monitoring, Rivers chemistry, Food Chain, Fluoxetine analogs & derivatives, Fluoxetine metabolism, Fluoxetine pharmacokinetics, Pharmaceutical Preparations metabolism, Brain metabolism, Water Pollutants, Chemical metabolism, Water Pollutants, Chemical pharmacokinetics, Fishes metabolism
- Abstract
Though bioaccumulation of pharmaceuticals by aquatic organisms continues to receive scientific attention, the internal disposition of these contaminants among different tissue compartments of fish species has been infrequently investigated, particularly among fish at different trophic positions. We tested a human to fish biological read-across hypothesis for contaminant disposition by examining tissue-specific accumulation in three understudied species, longnose gar (Lepisosteus osseus; piscivore), gizzard shad (Dorosoma cepedianum; planktivore/detritivore), and smallmouth buffalo (Ictiobus bubalus; benthivore), from a river influenced by municipal effluent discharge. In addition to surface water, fish plasma, and brain, gill, gonad, liver, and lateral muscle fillet tissues were analyzed via isotope dilution liquid chromatography tandem mass spectrometry. Caffeine and sucralose, two common effluent tracers, were quantitated at low micrograms per liter levels in surface water, while an anticonvulsant, carbamazepine, was observed at levels up to 37 ng/L. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and primary metabolites were detected in at least one tissue of all three species at low micrograms per kilogram concentrations. Within each species, brain and liver of select fish contained the highest levels of SSRIs compared to plasma and other tissues, which is generally consistent with human tissue disposition patterns. However, we observed differential accumulation among specific tissue types and species. For example, mean levels of sertraline in brain and liver tissues were 13.4 µg/kg and 1.5 µg/kg in gizzard shad and 1.3 µg/kg and 7.3 µg/kg in longnose gar, respectively. In contrast, smallmouth buffalo did not consistently accumulate SSRIs to detectable levels. Tissue-specific eco-exposome efforts are necessary to understand mechanisms associated with such marked bioaccumulation and internal dispositional differences among freshwater fish species occupying different trophic positions. Environ Toxicol Chem 2024;43:1894-1902. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)
- Published
- 2024
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4. Response Letter: Pharmacokinetic Profile of Caffeine and Its Two Main Metabolites in Dried Blood Spots After Five Different Oral Caffeine Administration Forms-A Randomized Crossover Study.
- Author
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Tuma C, Thomas A, Trede L, Braun H, and Thevis M
- Subjects
- Humans, Dried Blood Spot Testing methods, Administration, Oral, Male, Caffeine pharmacokinetics, Caffeine administration & dosage, Caffeine blood, Cross-Over Studies
- Published
- 2024
- Full Text
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5. Arsenite-Induced Drug-Drug Interactions in Rats.
- Author
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Zhang J, Li W, Liu Y, He Y, Cheng Z, Li X, Chen Y, Zhang A, Peng Y, and Zheng J
- Subjects
- Animals, Male, Rats, Intestinal Absorption drug effects, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Omeprazole pharmacology, Omeprazole pharmacokinetics, Midazolam pharmacokinetics, Caffeine pharmacokinetics, Chlorzoxazone pharmacokinetics, Metoprolol pharmacokinetics, Metoprolol pharmacology, Tolbutamide pharmacokinetics, Sodium Compounds toxicity, Sodium Compounds pharmacokinetics, Arsenites toxicity, Arsenites pharmacokinetics, Drug Interactions, Cytochrome P-450 Enzyme System metabolism, Rats, Sprague-Dawley
- Abstract
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for cytochrome P450 (CYP) s3A, 2C6, 2D, 2C11, 1A, and 2E, were selected as probe drugs for the pharmacokinetic study. Significant decreases in areas under the curves of probe substrates were observed in rats after consecutive 30-day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little change in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug-drug interactions. SIGNIFICANCE STATEMENT: Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents coadministered resulting from the observed drug-drug interactions. The present study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (areas under the curve) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
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- 2024
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6. Predicting gastric emptying of drug substances taken under postprandial conditions by combination of biorelevant dissolution and mechanistic in silico modeling.
- Author
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Winter F, Foja C, Feldmüller M, Kromrey ML, Schick P, Tzvetkov M, and Weitschies W
- Subjects
- Humans, Febuxostat pharmacokinetics, Febuxostat chemistry, Theobromine pharmacokinetics, Theobromine chemistry, Caffeine pharmacokinetics, Caffeine chemistry, Caffeine administration & dosage, Sildenafil Citrate pharmacokinetics, Sildenafil Citrate chemistry, Drug Liberation, Aspirin pharmacokinetics, Aspirin chemistry, Aspirin administration & dosage, Gastric Emptying physiology, Postprandial Period physiology, Models, Biological, Computer Simulation, Solubility
- Abstract
Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in C
max and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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7. Phenotype-Genotype Correlation Applying a Cocktail Approach and an Exome Chip Analysis Reveals Further Variants Contributing to Variation of Drug Metabolism.
- Author
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Böhm R, Bruckmueller H, Oswald S, Hübenthal M, Kaehler M, Ehmke L, Höcker J, Siegmund W, Franke A, and Cascorbi I
- Subjects
- Humans, Male, Female, Adult, Exome genetics, Caffeine pharmacokinetics, Caffeine metabolism, Dextromethorphan pharmacokinetics, Dextromethorphan metabolism, Losartan pharmacokinetics, Pharmaceutical Preparations metabolism, Young Adult, Omeprazole pharmacokinetics, Sex Factors, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Genetic Association Studies methods, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Genotype
- Abstract
Although great progress has been made in the fine-tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug-metabolizing enzymes., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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8. Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.
- Author
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Cheng Y, Du S, Hu H, Wang X, Carayannopoulos L, and Li Y
- Subjects
- Humans, Male, Middle Aged, Aged, Female, Myelodysplastic Syndromes drug therapy, Triazoles pharmacokinetics, Triazoles therapeutic use, Triazoles blood, Triazoles administration & dosage, Adult, Models, Biological, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents blood, Antineoplastic Agents therapeutic use, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase antagonists & inhibitors, Triazines, Leukemia, Myeloid, Acute drug therapy, Caffeine pharmacokinetics, Caffeine administration & dosage, Bayes Theorem, Drug Interactions, Aminopyridines pharmacokinetics, Aminopyridines therapeutic use
- Abstract
As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP) enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field., (© 2024, The American College of Clinical Pharmacology.)
- Published
- 2024
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9. Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1 G93A mouse model of amyotrophic lateral sclerosis following oral administration.
- Author
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Koehn LM, Jalaldeen R, Pelle J, and Nicolazzo JA
- Subjects
- Animals, Male, Female, Mice, Administration, Oral, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Digoxin pharmacokinetics, Digoxin administration & dosage, Sulfasalazine pharmacokinetics, Sulfasalazine administration & dosage, Intestinal Absorption drug effects, Intestinal Absorption physiology, Caffeine administration & dosage, Caffeine pharmacokinetics, Amyotrophic Lateral Sclerosis drug therapy, Amyotrophic Lateral Sclerosis metabolism, Spinal Cord metabolism, Spinal Cord drug effects, Brain metabolism, Brain drug effects, Disease Models, Animal, Mice, Transgenic
- Abstract
Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1
G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma ) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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10. Impact of advanced age on the gastric emptying of water under fasted and fed state conditions.
- Author
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Tzakri T, Senekowitsch S, Wildgrube T, Sarwinska D, Krause J, Schick P, Grimm M, Engeli S, and Weitschies W
- Subjects
- Humans, Adult, Aged, Male, Female, Young Adult, Saliva metabolism, Saliva chemistry, Aging physiology, Aged, 80 and over, Gastric Emptying physiology, Fasting physiology, Water metabolism, Caffeine administration & dosage, Caffeine pharmacokinetics
- Abstract
Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of
13 C3 -caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (p > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of Magenstrasse appears to follow a similar pattern in healthy older adults as in healthy younger adults., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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11. Prolongation of the gastric residence time of caffeine after administration in fed state: Comparison of effervescent granules with an extended release tablet.
- Author
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Foja C, Senekowitsch S, Winter F, Grimm M, Rosenbaum C, Koziolek M, Feldmüller M, Kromrey ML, Scheuch E, Tzvetkov MV, Weitschies W, and Schick P
- Subjects
- Humans, Male, Adult, Young Adult, Female, Fasting, Administration, Oral, Saliva metabolism, Saliva chemistry, Healthy Volunteers, Gastric Mucosa metabolism, Cross-Over Studies, Stomach drug effects, Caffeine administration & dosage, Caffeine pharmacokinetics, Delayed-Action Preparations pharmacokinetics, Delayed-Action Preparations administration & dosage, Tablets
- Abstract
The aim of the present study was to investigate the gastroretentive capacity of different formulation principles. This was indirectly determined by the absorption behavior of caffeine from the dosage forms. A slow and continuous appearance of caffeine in the saliva of healthy volunteers was used as a parameter for a prolonged gastric retention time. For this purpose, a four-way study was conducted with twelve healthy volunteers using the following test procedures: (1) Effervescent granules with 240 mL of still water administered in fed state, (2) effervescent granules with 20 mL of still water in fed state, (3) extended release (ER) tablet with 240 mL of still water in fed state, and (4) effervescent granules with 240 mL of still water in fasted state. The initial rise of the caffeine concentrations was more pronounced after the intake of the effervescent granules in the fed state compared to that of the ER tablets. However, t
max tended to be shorter in the fed study arms following administration of the ER tablet compared to the granules. Overall, the application of active pharmaceutical ingredients formulated as effervescent granules seems to be a promising approach to increase their gastric residence time after intake in fed state., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maximilian Feldmüller was an employee of the University of Greifswald during his contribution to this work and is now an employee of Bayer. Mirko Koziolek was an employee of the University of Greifswald during his contribution to this work and is now an employee of Abbvie., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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12. Impact of Viloxazine Extended-Release Capsules (Qelbree ® ) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.
- Author
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Wang Z, Liranso T, Maldonado-Cruz Z, Kosheleff AR, and Nasser A
- Subjects
- Female, Humans, Male, Caffeine pharmacokinetics, Caffeine administration & dosage, Capsules, Cytochrome P-450 Enzyme System drug effects, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Dextromethorphan pharmacokinetics, Dextromethorphan administration & dosage, Healthy Volunteers, Midazolam pharmacokinetics, Midazolam administration & dosage, Polymorphism, Genetic, Cytochrome P-450 CYP2D6 drug effects, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism, Delayed-Action Preparations, Viloxazine pharmacokinetics, Viloxazine administration & dosage
- Abstract
Background and Objective: Viloxazine extended-release (ER) [Qelbree
® ] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics., Methods: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers., Results: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax ), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt ), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞ ) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax , AUCt, and AUC∞ , respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax , AUCt, and AUC∞ , respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87))., Conclusion: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile., (© 2024. The Author(s).)- Published
- 2024
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13. Modeling Developmental Changes in Caffeine Clearance Considering Differences between Pre- and Postnatal Period.
- Author
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Ide H, Kawasaki Y, Tamura K, Yoshida T, Fujihara R, Hara A, and Taguchi M
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- Humans, Female, Infant, Newborn, Male, Pregnancy, Central Nervous System Stimulants blood, Central Nervous System Stimulants pharmacokinetics, Central Nervous System Stimulants administration & dosage, Caffeine blood, Caffeine pharmacokinetics, Caffeine administration & dosage, Gestational Age, Infant, Premature growth & development, Infant, Premature blood, Models, Biological
- Abstract
Taguchi et al. reported that postmenstrual age (PMA) is a promising factor in describing and understanding the developmental change of caffeine (CAF) clearance. The aim of the present study was to quantify how developmental changes occur and to determine the effect of the length of the gestational period on CAF clearance. We performed a nonlinear mixed effect model (NONMEM) analysis and evaluated the fit of six models. A total of 115 samples were obtained from 52 patients with a mean age of 34.3 ± 18.2 d. The median values of gestational age (GA) and postnatal age (PNA) were 196 and 31 d, respectively. Serum CAF levels corrected for dose per body surface area (BSA) (C/D ratio
BSA ) were dependent on PMA rather than PNA, which supports the findings of a previous study. NONMEM analysis provided the following final model of oral clearance: CL/F = 0.00603∙WT∙∙0.877GA ≤ 196 L/h. This model takes into account developmental changes during prenatal and postnatal periods separately. The model successfully described the variation in clearance of CAF. Our findings suggest that the dosage of CAF in preterm infants should be determined based not only on body weight (WT) but also on both PNA and GA.- Published
- 2024
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14. Caffeine-loaded nano/micro-carriers: Techniques, bioavailability, and applications.
- Author
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Shaddel R, Akbari-Alavijeh S, Cacciotti I, Yousefi S, Tomas M, Capanoglu E, Tarhan O, Rashidinejad A, Rezaei A, Bhia M, and Jafari SM
- Subjects
- Humans, Drug Carriers chemistry, Functional Food, Emulsions chemistry, Dietary Supplements, Caffeine chemistry, Caffeine pharmacokinetics, Caffeine administration & dosage, Biological Availability, Nanoparticles chemistry
- Abstract
Caffeine, as one of the most consumed bioactive compounds globally, has gained considerable attention during the last years. Considering the bitter taste and adverse effects of high levels of caffeine consumption, it is crucial to apply a strategy for masking the caffeine's bitter taste and facilitating its programmable deliverance within a long time. Other operational parameters such as food processing parameters, exposure to sunlight and oxygen, and gastrointestinal digestion could also degrade the phenolic compounds in general and caffeine in special. To overcome these challenges, various nano/micro-platforms have been fabricated, including lipid-based (e.g., nanoliposomal vehicles; nanoemulsions, double emulsions, Pickering emulsions; microemulsions; niosomal vehicles; solid lipid nanoparticles and nanostructured lipid carriers), as well as biopolymeric (e.g., nanoparticles; hydrogels, organogels, oleogels; nanofibers and nanotubes; protein-polysaccharide nanocomplexes, conjugates; cyclodextrin inclusion complexes) and inorganic (e.g., gold and silica nanoparticles) nano/micro-structures. In this review, the findings on various caffeine-loaded nano/micro-carriers and their potential applications in functional food products/supplements will be discussed. Also, the controlled release and bioavailability of encapsulated caffeine will be given, and finally, the toxicity and safety of encapsulated caffeine will be presented.
- Published
- 2024
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15. Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.
- Author
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Bansal S, Zamarripa CA, Spindle TR, Weerts EM, Thummel KE, Vandrey R, Paine MF, and Unadkat JD
- Subjects
- Humans, Adult, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP2C19, Caffeine pharmacokinetics, Midazolam pharmacokinetics, Cytochrome P-450 CYP3A, Losartan, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Cytochrome P-450 CYP2D6, Drug Interactions, Omeprazole pharmacokinetics, Plant Extracts pharmacokinetics, Dronabinol pharmacology, Cannabinoids pharmacology, Cannabis, Cannabidiol, Hallucinogens
- Abstract
Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUC
GMR ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2023
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16. Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.
- Author
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Liu J, Solan R, Wolk R, Plotka A, O'Gorman MT, Winton JA, Kaplan J, and Purohit VS
- Subjects
- Humans, Healthy Volunteers, Drug Interactions, Area Under Curve, Caffeine pharmacokinetics, Cytochrome P-450 CYP1A2 metabolism
- Abstract
Aims: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate., Methods: In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8 days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments., Results: Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants., Conclusion: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates., (© 2023 British Pharmacological Society.)
- Published
- 2023
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17. Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.
- Author
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Chen X, Isambert N, López-López R, Giovannini M, Pognan N, Kapoor S, Quinlan M, You B, Cui X, Rahmanzadeh G, and Mau-Sorensen M
- Subjects
- Humans, Midazolam pharmacokinetics, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System metabolism, Area Under Curve, Drug Interactions, Cytochrome P-450 CYP1A2 metabolism, Caffeine pharmacokinetics
- Abstract
Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety., Methods: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator., Results: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (C
max ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study., Conclusion: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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18. Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro Analyses and an Open-Label, Single-Sequence Phase I Study.
- Author
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Desch M, Schlecker C, Hohl K, Liesenfeld KH, Chan T, Müller F, Wunderlich G, Keller S, Ishiguro N, and Wind S
- Subjects
- Humans, Male, Cytochrome P-450 CYP2C19, ATP Binding Cassette Transporter, Subfamily B, Member 1, Cytochrome P-450 CYP3A, Warfarin, Cross-Over Studies, Cytochrome P-450 CYP2C9, Caco-2 Cells, Caffeine pharmacokinetics, Drug Interactions, Cytochrome P-450 Enzyme System metabolism, Omeprazole pharmacokinetics, ATP Binding Cassette Transporter, Subfamily B, Digoxin pharmacokinetics, Area Under Curve, Glycine Plasma Membrane Transport Proteins, Midazolam
- Abstract
Purpose/background: Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809., Methods/procedures: Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively. Pharmacokinetic characteristics of probe drugs were subsequently assessed in a Phase I, open-label, single-sequence crossover study in healthy male participants. Participants received a probe-drug cocktail containing midazolam (CYP3A4), warfarin (CYP2C9), and omeprazole (CYP2C19) and a separate dose of digoxin (P-gp), alone and on a background of steady-state BI 425809 25 mg once daily in 2 treatment periods. Adverse events were monitored., Findings/results: In vitro assays revealed concentration-dependent induction of CYP3A4 and inhibition of P-gp by BI 425809. In the clinical study, 12 of 13 participants completed both periods. With BI 425809, area under the plasma concentration curve from administration to the last measurement (AUC 0-tz ) and maximum plasma concentration ( Cmax ) for midazolam were lower than when administered alone. Adjusted geometric mean ratios (90% confidence interval) were 70.6% (63.9%-78.1%) for AUC 0-tz and 77.6% (67.3%-89.4%) for Cmax . For warfarin and digoxin, AUC 0-tz and Cmax were similar with and without BI 425809. For omeprazole, BI 425809 slightly reduced AUC 0-tz but not Cmax versus omeprazole alone. No new safety signals were identified., Implications/conclusions: These findings indicate induction of CYP3A4 by once-daily BI 425809 25 mg (the assumed highest therapeutic dose) and no meaningful effects on CYP2C9, CYP2C19, or P-gp in vivo., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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19. Pharmacokinetic Interactions of a Licorice Dietary Supplement with Cytochrome P450 Enzymes in Female Participants.
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Liu J, Banuvar S, Viana M, Barengolts E, Chen SN, Pauli GF, and van Breemen RB
- Subjects
- Humans, Female, Cytochrome P-450 CYP2D6, Caffeine pharmacokinetics, Cytochrome P-450 CYP3A, Tolbutamide, Glycyrrhizic Acid, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System, Dietary Supplements, Cytochrome P-450 CYP1A2, Glycyrrhiza chemistry
- Abstract
Licorice, the roots and rhizomes of Glycyrrhiza glabra L., has been used as a medicinal herb, herbal adjuvant, and flavoring agent since ancient times. Recently, licorice extracts have become popular as dietary supplements used by females to alleviate menopausal symptoms. Exposure to licorice products containing high levels of glycyrrhizic acid can cause hypokalemia, but independent from this effect, preclinical data indicate that licorice can inhibit certain cytochrome P450 (P450) enzymes. To evaluate whether clinically relevant pharmacokinetic interactions of licorice with P450 enzymes exist, a phase 1 clinical investigation was carried out using a licorice extract depleted in glycyrrhizic acid (content <1%) and a cocktail containing caffeine, tolbutamide, alprazolam, and dextromethorphan, which are probe substrates for the enzymes CYP1A2, CYP2C9, CYP3A4/5, and CYP2D6, respectively. The botanically authenticated and chemically standardized extract of roots from G. glabra was consumed by 14 healthy menopausal and postmenopausal female participants twice daily for 2 weeks. The pharmacokinetics of each probe drug were evaluated immediately before and after supplementation with the licorice extract. Comparison of the average areas under the time-concentration curves (AUCs) for each probe substrate in serum showed no significant changes from licorice consumption, whereas time to reach peak concentration for caffeine and elimination half-life for tolbutamide showed small changes. According to the US Food and Drug Administration guidance, which is based on changes in the AUC of each probe substrate drug, the investigated licorice extract should not cause any clinically relevant pharmacokinetic interactions with respect to CYP3A4/5, CYP2C9, CYP2D6, or CYP1A2. SIGNIFICANCE STATEMENT: Despite generally-recognized-as-safe status, the licorice species Glycyrrhiza glabra has been associated with some toxicity. Preclinical studies suggest that G. glabra might cause pharmacokinetic drug interactions by inhibiting several cytochrome P450 enzymes. This phase 1 clinical study addressed these concerns by evaluating clinically relevant effects with respect to CYP3A4/5, CYP2C9, CYP2D6, and CYP1A2. These results showed that a standardized G. glabra extract did not cause any clinically relevant pharmacokinetic drug interactions with four major cytochrome P450 enzymes., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2023
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20. The Effect of Caffeine Ingestion during Evening Exercise on Subsequent Sleep Quality in Females.
- Author
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Ali, A., O'Donnell, J. M., Starck, C., and Rutherfurd-Markwick, K. J.
- Subjects
- *
ANALYSIS of variance , *BODY weight , *CAFFEINE , *CROSSOVER trials , *EXERCISE , *QUESTIONNAIRES , *RUNNING , *SLEEP , *STATISTICS , *T-test (Statistics) , *TIME , *DATA analysis , *TREADMILLS , *RANDOMIZED controlled trials , *REPEATED measures design , *BLIND experiment , *DATA analysis software , *DESCRIPTIVE statistics , *ONE-way analysis of variance - Abstract
In a randomised, double-blind, placebo-controlled crossover design, 10 females taking monophasic oral contraceptives completed 90min intermittent treadmill-running 45min after ingestion of 6mg⋅kg-1 body mass anhydrous caffeine or artificial sweetener (placebo). Water (3mL⋅kg-1) was provided every 15min during exercise. Venous blood samples were taken before, during and after exercise, as well as after sleep (~15h post-ingestion), and levels of caffeine, paraxanthine, theobromine and theophylline were measured using high-performance liquid chromatography. Sleep quality was assessed using the Leeds Sleep Evaluation Questionnaire. Plasma caffeine concentration peaked 100min after ingestion. Caffeine clearance was 0.95±0.14mL⋅min-1⋅g-1 while the elimination half-life of caffeine was 17.63 ± 8.06 h. Paraxanthine and theophylline levels were significantly elevated at 15h with no significant change in theobromine. Sleep latency and subsequent quality of sleep was impaired following caffeine supplementation (P<0.05); there were no differences between trials for how participants were feeling upon awakening. This is the first controlled study to examine caffeine supplementation on sleep quality in female athletes taking a low-dose monophasic oral contraceptive steroid following an intermittent-exercise running protocol. The data shows that female athletes using monophasic oral contraceptive steroids will have impaired sleep quality following evening caffeine ingestion. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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21. Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism.
- Author
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Albadry M, Höpfl S, Ehteshamzad N, König M, Böttcher M, Neumann J, Lupp A, Dirsch O, Radde N, Christ B, Christ M, Schwen LO, Laue H, Klopfleisch R, and Dahmen U
- Subjects
- Mice, Animals, Caffeine pharmacokinetics, Metabolic Clearance Rate, Cytochrome P-450 Enzyme System metabolism, Midazolam pharmacology, Fatty Liver
- Abstract
Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms., (© 2022. The Author(s).)
- Published
- 2022
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22. A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects.
- Author
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Sherman MM, Tarantino PM, Morrison DN, Lin CH, Parente RM, and Sippy BC
- Subjects
- Adult, Area Under Curve, Chromatography, Liquid, Cross-Over Studies, Cytochrome P-450 Enzyme System, Double-Blind Method, Healthy Volunteers, Humans, Tandem Mass Spectrometry, Caffeine analogs & derivatives, Caffeine pharmacokinetics
- Abstract
The deuterium kinetic isotope effect has been used to affect the cytochrome P450 metabolism of the deuterated versions of substances. This study compares the pharmacokinetics of caffeine, a Generally Recognized As Safe food and beverage ingredient, versus d9-caffeine, a potential caffeine alternative, and their respective metabolites at two dose levels in 20 healthy adults. A single dose of 50 mg or 250 mg of caffeine, or a molar-equivalent dose of d9-caffeine, were orally administered in solution with blood samples collected for up to 48 h post-dose. Plasma concentrations of parent and metabolites were analyzed using validated LC-MS/MS methods. Both d9-caffeine and caffeine were rapidly absorbed; however, d9-caffeine exhibited a higher (ca. 29%-43%) C
max and 4-5-fold higher AUClast than caffeine, and lower Cmax , lower AUClast , and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine. Results were consistent in normal and rapid metabolizers, and both substances were well tolerated., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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23. Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently.
- Author
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Duthaler U, Bachmann F, Suenderhauf C, Grandinetti T, Pfefferkorn F, Haschke M, Hruz P, Bouitbir J, and Krähenbühl S
- Subjects
- Caffeine pharmacokinetics, Child, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C9, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 CYP3A metabolism, Cytochrome P-450 Enzyme System metabolism, Humans, Liver Cirrhosis, Metoprolol, Midazolam pharmacokinetics, Omeprazole, Cytochrome P-450 CYP1A2 metabolism, Flurbiprofen pharmacokinetics
- Abstract
Background: Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking., Objective: In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach., Methods: We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12)., Results: While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged., Conclusions: Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis., Clinical Trial Registration: NCT03337945., (© 2022. The Author(s).)
- Published
- 2022
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24. Measurements of caffeine and plasma metabolite/caffeine ratios as a test for hepatic drug-oxidizing capacity in goats.
- Author
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Uney, Kamil, Tumer, Ilyas, and Traş, Bünyamin
- Subjects
- *
PHYSIOLOGICAL effects of caffeine , *ALKALOIDS , *METABOLITES , *PHARMACOKINETICS , *DRUG administration , *DATA analysis , *GOATS as laboratory animals - Abstract
The aim of this investigation was to determine the pharmacokinetics and demethylation of caffeine (CF) and the metabolite/CF ratios that correlated best with CF clearance, which were used to evaluate hepatic drug-oxidizing capacity of CF after a single intravenous dose (5 mg/kg) in hair goats (n = 9). Pharmacokinetic parameters of CF and its metabolites, theobromine (TB), paraxanthine (PX) and theophylline (TP), were calculated. The plasma metabolic ratios TB/CF, PX/CF, TP/CF and TB+PX+TP/CF were determined at 6, 8 and 10 h after CF administration to evaluate their hepatic drug-oxidizing capacity. The plasma concentration–time data of CF were fit to a two-compartment model in all animals. The clearance of CF was 0.08 ± 0.02 L/h/kg, and the volume of distribution was 0.91 ± 0.16 L/kg. The demethylation fractions of CF to TB, PX and TP were 0.24, 0.37 and 0.39, respectively. Correlations between the metabolic ratios and CF clearance were quite high, except for the PX/CF ratio, particularly at 6 h (r = 0.650–0.750, P < 0.01, 0.05) and 10 h (r = 0.650–0.767, P < 0.01, 0.05). Plasma metabolite/CF ratios, except for the PX/CF ratio, may be useful as an alternative to measurements of CF clearance for the determination of the hepatic drug-oxidizing capacity in goats. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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25. Central Nervous System Stimulants Limit Caffeine Transport at the Blood-Cerebrospinal Fluid Barrier.
- Author
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Ikeda-Murakami K, Tani N, Ikeda T, Aoki Y, and Ishikawa T
- Subjects
- Autopsy, Biological Transport, Blood-Brain Barrier chemistry, Case-Control Studies, Cells, Cultured, Choroid Plexus cytology, Endothelial Cells chemistry, Endothelial Cells cytology, Endothelium, Vascular cytology, Humans, Models, Biological, 4-Aminopyridine pharmacology, Caffeine pharmacokinetics, Central Nervous System Stimulants pharmacology, Cerebrospinal Fluid chemistry, Choroid Plexus chemistry, Endothelium, Vascular chemistry
- Abstract
Caffeine, a common ingredient in energy drinks, crosses the blood-brain barrier easily, but the kinetics of caffeine across the blood-cerebrospinal fluid barrier (BCSFB) has not been investigated. Therefore, 127 autopsy cases (Group A, 30 patients, stimulant-detected group; and Group B, 97 patients, no stimulant detected group) were examined. In addition, a BCSFB model was constructed using human vascular endothelial cells and human choroid plexus epithelial cells separated by a filter, and the kinetics of caffeine in the BCSFB and the effects of 4-aminopyridine (4-AP), a neuroexcitatory agent, were studied. Caffeine concentrations in right heart blood (Rs) and cerebrospinal fluid (CSF) were compared in the autopsy cases: caffeine concentrations were higher in Rs than CSF in Group A compared to Group B. In the BCSFB model, caffeine and 4-AP were added to the upper layer, and the concentration in the lower layer of choroid plexus epithelial cells was measured. The CSF caffeine concentration was suppressed, depending on the 4-AP concentration. Histomorphological examination suggested that choroid plexus epithelial cells were involved in inhibiting the efflux of caffeine to the CSF. Thus, the simultaneous presence of stimulants and caffeine inhibits caffeine transfer across the BCSFB.
- Published
- 2022
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26. Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine.
- Author
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Parente RM, Tarantino PM, Sippy BC, and Burdock GA
- Subjects
- Administration, Oral, Animals, Bacteria drug effects, Bacteria genetics, Brain metabolism, Caffeine administration & dosage, Caffeine blood, DNA Damage drug effects, Deuterium chemistry, Deuterium metabolism, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Caffeine pharmacokinetics
- Abstract
Altering caffeine's negative physiological effects and extending its duration of activity is an active area of research; however, deuteration as a means of achieving these goals is unexplored. Deuteration substitutes one or more of the hydrogen atoms of a substance with deuterium, a stable isotope of hydrogen that contains an extra neutron. Deuteration can potentially alter the metabolic profile of a substance, while maintaining its pharmacodynamic properties. d9-Caffeine is a deuterated isotopologue of caffeine with the nine hydrogens contained in the 1, 3, and 7 methyl groups of caffeine substituted with deuterium. d9-Caffeine may prove to be an alternative to caffeine that may be consumed with less frequency, at lower doses, and with less exposure to downstream active metabolites of caffeine. Characterization of d9-caffeine's genotoxic potential, pharmacodynamic, and pharmacokinetic behavior is critical in establishing how it may differ from caffeine. d9-Caffeine was non-genotoxic with and without metabolic activation in both a bacterial reverse mutation assay and a human mammalian cell micronucleus assay at concentrations up to the ICH concentration limits. d9-Caffeine exhibited a prolonged systemic and brain exposure time in rats as compared to caffeine following oral administration. The adenosine receptor antagonist potency of d9-caffeine was similar to caffeine., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2022
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27. A Phase 1 Open-Label, Fixed-Sequence Pharmacokinetic Drug Interaction Trial to Investigate the Effect of Cannabidiol on the CYP1A2 Probe Caffeine in Healthy Subjects.
- Author
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Thai C, Tayo B, and Critchley D
- Subjects
- Adult, Caffeine metabolism, Central Nervous System Stimulants metabolism, Female, Humans, Male, Young Adult, Anticonvulsants pharmacology, Caffeine pharmacokinetics, Cannabidiol pharmacology, Central Nervous System Stimulants pharmacokinetics, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP1A2 Inhibitors pharmacology, Drug Interactions, Theophylline metabolism
- Abstract
This pharmacokinetic (PK) drug-interaction trial investigated the effects of repeated dosing of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the United States and Epidyolex in Europe; 100 mg/mL oral solution) on caffeine clearance via modulation of cytochrome P450 (CYP) 1A2 activity in healthy adults. In this phase 1 open-label, fixed-sequence trial, all subjects received a single 200 mg caffeine dose and placebo on day 1. Subjects then titrated CBD from 250 mg once daily to 750 mg twice daily between days 3 and 11 and took 750 mg CBD twice daily between days 12 and 27. On day 26, subjects received a single 200-mg caffeine dose with their morning CBD dose. Plasma concentrations of caffeine and its CYP1A2-mediated metabolite, paraxanthine, were determined on days 1 and 26 and PK parameters derived using noncompartmental analysis. Safety was monitored throughout. Sixteen subjects enrolled, and 9 completed treatment. When caffeine was administered with steady-state CBD, caffeine exposure increased by 15% for C
max and 95% for AUC0-∞ , tmax increased from 1.5 to 3.0 hours, and t1/2 increased from 5.4 to 10.9 hours compared with caffeine administered with placebo. Under the same conditions, paraxanthine exposure decreased by 22% for Cmax and increased by 18% for AUC0-∞ , tmax increased from 8.0 to 14.0 hours, and t1/2 increased from 7.2 to 13.7 hours. Overall, there were no unexpected adverse events; diarrhea was most common, and 6 subjects discontinued because of elevated liver transaminases. These data suggest that CBD is an inhibitor of CYP1A2., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2021
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28. A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.
- Author
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Dornbierer DA, Yerlikaya F, Wespi R, Boxler MI, Voegel CD, Schnider L, Arslan A, Baur DM, Baumgartner MR, Binz TM, Kraemer T, and Landolt HP
- Subjects
- Adult, Caffeine pharmacokinetics, Emotions drug effects, Female, Healthy Volunteers, Humans, Hydrocortisone administration & dosage, Male, Polysomnography, Psychomotor Performance drug effects, Sleep Stages, Time Factors, Young Adult, Caffeine administration & dosage, Sleep drug effects, Wakefulness drug effects
- Abstract
Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360., (© 2021. The Author(s).)
- Published
- 2021
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29. Influence of nanocrystal size on the in vivo absorption kinetics of caffeine after topical application.
- Author
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Breuckmann P, Meinke MC, Jaenicke T, Krutmann J, Rasulev U, Keck CM, Müller RH, Klein AL, Lademann J, and Patzelt A
- Subjects
- Administration, Cutaneous, Adult, Area Under Curve, Biological Availability, Caffeine pharmacokinetics, Hair Follicle metabolism, Humans, Male, Middle Aged, Particle Size, Skin metabolism, Time Factors, Caffeine administration & dosage, Nanoparticles, Skin Absorption
- Abstract
The absorption of topically applied substances is challenging due to the effective skin barrier. Encapsulation of substances into nanoparticles was expected to be promising to increase the bioavailability of topically applied products. Since nanoparticles cannot traverse the intact skin barrier, but penetrate into the hair follicles, they could be used to deliver substances via hair follicles, where the active is released and can translocate independently transfollicularly into the viable epidermis. In the present in vivo study, this effect was investigated for caffeine. Caffeine nanocrystals of two sizes, 206 nm and 694 nm, with equal amounts of caffeine were used to study caffeine serum concentration kinetics after topical application on 5 human volunteers. The study demonstrated that at early time points, the smaller nanocrystals were more effective in increasing the bioavailability of caffeine, whereas after 20 min, the serum concentration of caffeine was higher when caffeine was applied by larger nanocrystals. Caffeine was still detectable after 5 days. The area under the curve could be increased by 82% when the 694 nm nanocrystals were applied. Especially larger sized nanocrystals seem to be a promising type of nanoparticulate preparation to increase the bioavailability of topically applied drugs via the transfollicular penetration pathway., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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30. Massive suicidal ingestion of caffeine: a case report with investigation of the cardiovascular effect/concentration relationships.
- Author
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Grémain V, Chevillard L, Saussereau E, Schnell G, and Mégarbane B
- Subjects
- Administration, Oral, Adrenergic alpha-Agonists administration & dosage, Adrenergic beta-1 Receptor Antagonists administration & dosage, Caffeine administration & dosage, Caffeine pharmacokinetics, Cardiotoxicity, Central Nervous System Stimulants administration & dosage, Central Nervous System Stimulants pharmacokinetics, Electric Countershock, Half-Life, Humans, Hyperlactatemia chemically induced, Infusions, Intravenous, Intubation, Intratracheal, Male, Metabolic Clearance Rate, Middle Aged, Norepinephrine administration & dosage, Powders, Propanolamines administration & dosage, Tachycardia diagnosis, Tachycardia physiopathology, Tachycardia therapy, Treatment Outcome, Ventricular Fibrillation diagnosis, Ventricular Fibrillation physiopathology, Ventricular Fibrillation therapy, Caffeine poisoning, Central Nervous System Stimulants poisoning, Heart Rate drug effects, Suicide, Attempted, Tachycardia chemically induced, Ventricular Fibrillation chemically induced
- Abstract
Background: Caffeine poisoning may cause life-threatening arrhythmias and hemodynamic failure. We aimed to investigate the toxicokinetics (TK), toxicodynamics (TD) and TK/TD relationships of caffeine in a case of poisoning., Case Report: A 47-year-old male ingested pure anhydrous caffeine powder (70 g) in a suicide attempt. He developed agitation, tachycardia, and two episodes of ventricular fibrillation treated with defibrillation and tracheal intubation. He was successfully managed using intravenous infusions of esmolol and norepinephrine., Methods: We modelled the time-course of plasma caffeine concentration (TK study using online liquid chromatography-tandem mass spectrometry), the time-course of blood lactate concentration and infusion rates of esmolol and norepinephrine (TD studies) and the TK/TD relationships., Results: Caffeine TK was of first-order peaking at 258 mg/L with an elimination half-life of 46.2 h and clearance of 2.2 L/h. Caffeine-related effects on blood lactate (peak, 10 mmol/L at 1.25 h postingestion) were described by a Bateman-type equation (formation rate, 0.05 mmol/mg.h; elimination rate, 0.9 mmol/mg.h). Esmolol and norepinephrine infusion rates to reverse caffeine-related cardiovascular effects (peaks at 51-h postingestion) fitted well with a sigmoidal E
max model (EC50 , 180.0 and 225.9 mg/L, respectively; Hill coefficient, 10.0)., Conclusion: Massive caffeine ingestion is characterized by prolonged caffeine elimination. TK/TD relationships are helpful to quantify caffeine-related catecholaminergic effects.- Published
- 2021
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31. Pharmacokinetics of Caffeine and Its Demethylated Metabolites in Lactation: Predictions of Milk to Serum Concentration Ratios.
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Oo, Cheah, Burgio, David, Kuhn, Robert, Desai, Nirmala, and McNamara, Patrick
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- 1995
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32. Caffeine as a Factor Influencing the Functioning of the Human Body-Friend or Foe?
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Rodak K, Kokot I, and Kratz EM
- Subjects
- Adolescent, Adult, Analgesics, Animals, Antioxidants, Caffeine pharmacokinetics, Cardiovascular System drug effects, Central Nervous System Stimulants, Child, Digestive System drug effects, Humans, Immune System drug effects, Mental Disorders drug therapy, Neurodegenerative Diseases drug therapy, Receptors, Purinergic P1, Respiratory System drug effects, Urinary Tract drug effects, Caffeine adverse effects, Caffeine pharmacology
- Abstract
Nowadays, caffeine is one of the most commonly consumed substances, which presents in many plants and products. It has both positive and negative effects on the human body, and its activity concerns a variety of systems including the central nervous system, immune system, digestive system, respiratory system, urinary tract, etc. These effects are dependent on quantity, the type of product in which caffeine is contained, and also on the individual differences among people (sex, age, diet etc.). The main aim of this review was to collect, present, and analyze the available information including the latest discoveries on the impact of caffeine on human health and the functioning of human body systems, taking into account the role of caffeine in individual disease entities. We present both the positive and negative sides of caffeine consumption and the healing properties of this purine alkaloid in diseases such as asthma, Parkinson's disease, and others, not forgetting about the negative effects of excess caffeine (e.g., in people with hypertension, children, adolescents, and the elderly). In summary, we can conclude, however, that caffeine has a multi-directional influence on various organs of the human body, and because of its anti-oxidative properties, it was, and still is, an interesting topic for research studies including those aimed at developing new therapeutic strategies.
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- 2021
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33. Effects of Caffeine on Splanchnic Oxygenation in Preterm Infants.
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Ilhan O and Bor M
- Subjects
- Caffeine pharmacokinetics, Citrates pharmacokinetics, Female, Gestational Age, Humans, Infant, Newborn, Infant, Premature, Male, Prospective Studies, Spectroscopy, Near-Infrared, Caffeine administration & dosage, Citrates administration & dosage, Oxygen Saturation drug effects, Splanchnic Circulation drug effects
- Abstract
Objective: The aim of this study is to assess the effects of administering 20 mg/kg loading dose of caffeine citrate intravenously on splanchnic oxygenation in preterm infants., Study Design: The infants with a gestational age (GA) of <34 weeks who were administered with a 20 mg/kg intravenous loading dose of caffeine citrate within 48 hours after birth were investigated prospectively. Regional splanchnic oxygen saturation (rsSO
2 ) and splanchnic fractional tissue oxygen extraction rate (sFTOE) were measured using near-infrared spectroscopy before caffeine infusion, immediately after caffeine infusion and 1, 2, 3, 4, and 6 hours (h) after dose completion; postdose values were compared with predose values., Results: A total of 41 infants with a mean GA of 29.2 ± 1.6 weeks and birth weight of 1,315 ± 257 g as well as postnatal age of 32.2 ± 10.8 hours were included in the study. rsSO2 significantly reduced from 63.1 to 57.5% immediately after caffeine infusion, 55.1% after 1 hour, and 55.2% after 2 hours with partial recovery at 3-hour postdose. sFTOE increased correspondingly., Conclusion: Caffeine reduces splanchnic oxygenation and increases splanchnic oxygen extraction for at least 2 hours with partial recovery to predose levels at 3-hour postdose., Competing Interests: None declared., (Thieme. All rights reserved.)- Published
- 2021
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34. Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.
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Dai X, Karol MD, Hitron M, Hard ML, Goulet MT, McLaughlin CF, and Brantley SJ
- Subjects
- Administration, Oral, Adult, Benzofurans pharmacokinetics, Bupropion administration & dosage, Bupropion pharmacokinetics, Caffeine administration & dosage, Caffeine pharmacokinetics, Dextromethorphan administration & dosage, Dextromethorphan pharmacokinetics, Drug Interactions, Female, Flurbiprofen administration & dosage, Flurbiprofen pharmacokinetics, Gene Expression Regulation drug effects, Half-Life, Healthy Volunteers, Humans, Male, Midazolam administration & dosage, Midazolam pharmacokinetics, Naphthoquinones pharmacokinetics, Omeprazole administration & dosage, Omeprazole pharmacokinetics, Rosuvastatin Calcium administration & dosage, Rosuvastatin Calcium pharmacokinetics, Young Adult, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Benzofurans administration & dosage, Cytochrome P-450 Enzyme System metabolism, Naphthoquinones administration & dosage, Neoplasm Proteins metabolism
- Abstract
Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
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- 2021
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35. Data-driven personalization of a physiologically based pharmacokinetic model for caffeine: A systematic assessment.
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Fendt R, Hofmann U, Schneider ARP, Schaeffeler E, Burghaus R, Yilmaz A, Blank LM, Kerb R, Lippert J, Schlender JF, Schwab M, and Kuepfer L
- Subjects
- Adolescent, Adult, Caffeine administration & dosage, Computer Simulation, Dose-Response Relationship, Drug, Female, Glomerular Filtration Rate, Humans, Liver blood supply, Liver diagnostic imaging, Magnetic Resonance Imaging, Male, Middle Aged, Phenotype, Precision Medicine, Young Adult, Caffeine pharmacokinetics, Cytochrome P-450 CYP1A2 metabolism, Models, Biological
- Abstract
Physiologically based pharmacokinetic (PBPK) models have been proposed as a tool for more accurate individual pharmacokinetic (PK) predictions and model-informed precision dosing, but their application in clinical practice is still rare. This study systematically assesses the benefit of using individual patient information to improve PK predictions. A PBPK model of caffeine was stepwise personalized by using individual data on (1) demography, (2) physiology, and (3) cytochrome P450 (CYP) 1A2 phenotype of 48 healthy volunteers participating in a single-dose clinical study. Model performance was benchmarked against a caffeine base model simulated with parameters of an average individual. In the first step, virtual twins were generated based on the study subjects' demography (height, weight, age, sex), which implicated the rescaling of average organ volumes and blood flows. The accuracy of PK simulations improved compared with the base model. The percentage of predictions within 0.8-fold to 1.25-fold of the observed values increased from 45.8% (base model) to 57.8% (Step 1). However, setting physiological parameters (liver blood flow determined by magnetic resonance imaging, glomerular filtration rate, hematocrit) to measured values in the second step did not further improve the simulation result (59.1% in the 1.25-fold range). In the third step, virtual twins matching individual demography, physiology, and CYP1A2 activity considerably improved the simulation results. The percentage of data within the 1.25-fold range was 66.15%. This case study shows that individual PK profiles can be predicted more accurately by considering individual attributes and that personalized PBPK models could be a valuable tool for model-informed precision dosing approaches in the future., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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36. Single high-dose peroral caffeine intake inhibits ultraviolet radiation-induced apoptosis in human lens epithelial cells in vitro.
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Kronschläger M, Ruiß M, Dechat T, and Findl O
- Subjects
- Administration, Oral, Aged, Apoptosis drug effects, Apoptosis radiation effects, Caffeine pharmacokinetics, Cataract metabolism, Cataract pathology, Central Nervous System Stimulants administration & dosage, Central Nervous System Stimulants pharmacokinetics, Epithelial Cells drug effects, Epithelial Cells pathology, Female, Follow-Up Studies, Humans, Lens, Crystalline drug effects, Lens, Crystalline pathology, Male, Pilot Projects, Prospective Studies, Radiation Injuries complications, Radiation Injuries metabolism, Caffeine administration & dosage, Cataract etiology, Epithelial Cells radiation effects, Lens, Crystalline radiation effects, Radiation Injuries pathology, Ultraviolet Rays adverse effects
- Abstract
Purpose: The aim of the present study was to determine whether caffeine concentrations in human lens epithelial cells (LECs) achieved from acute peroral caffeine intake inhibit ultraviolet radiation-induced apoptosis in vitro., Methods: Patients were planned for cataract surgery of both eyes with a caffeine abstinence of 2 weeks in total, starting 1 week before surgery of the first eye. The second eye was scheduled 1 week after the first eye. At the day of the second eye surgery, patients were given coffee containing 180 mg caffeine shortly before surgery. Lens capsules including LEC, harvested after capsulorhexis, were transferred to a cell culture dish and immediately exposed to close to threshold ultraviolet radiation (UVR). At 24 hr after UVR exposure, apoptotic LECs were analysed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining., Results: TUNEL-positive cells were detected in UVR-exposed lens capsules both after caffeine intake and in controls. The mean difference in TUNEL-positive cells between caffeine intake and contralateral controls (no caffeine) resulted in a 95% CI 15.3 ± 10.4% (degrees of freedom: 16)., Conclusion: Peroral caffeine consumption significantly decreased UVR-induced apoptosis in LEC supporting epidemiological findings that caffeine delays the onset of cataract., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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37. Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase I Clinical Trial.
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Watkins PB, Church RJ, Li J, and Knappertz V
- Subjects
- Adult, Caffeine pharmacokinetics, Cannabidiol administration & dosage, Cannabidiol pharmacokinetics, Chemical and Drug Induced Liver Injury blood, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP2C19 genetics, Drug Interactions, Female, Humans, Male, Alanine Transaminase blood, Cannabidiol adverse effects, Chemical and Drug Induced Liver Injury etiology
- Abstract
Liver safety concerns were raised in randomized controlled trials of cannabidiol (CBD) in patients with Lennox-Gastaut and Dravet syndromes, but the relevance of these concerns to healthy adults consuming CBD is unclear. The objective of this manuscript is to report on liver safety findings from healthy adults who received therapeutic daily doses of CBD for ~ 3.5 weeks and to investigate any correlation between transaminase elevations and baseline characteristics, pharmacogenetic, and pharmacokinetic data. Sixteen healthy adults were enrolled in a phase I, open-label, fixed single-sequence drug-drug interaction trial to investigate the effect of repeated dose administration of CBD (1,500 mg/day) on cytochrome P450 (CYP) 1A2 activity. Seven (44%) participants experienced peak serum alanine aminotransferase (ALT) values greater than the upper limit of normal (ULN). For five (31%) participants, the value exceeded 5 × ULN, therefore meeting the international consensus criteria for drug-induced liver injury. There was no correlation between transaminase elevations and baseline characteristics, CYP2C19 genotype, or CBD plasma concentrations. All ALT elevations above the ULN began within 2-4 weeks of initial exposure to CBD. Among the six participants with ALT elevations who were discontinued from the protocol, some had symptoms consistent with hepatitis or hypersensitivity. We conclude that healthy adults consuming CBD may experience elevations in serum ALT consistent with drug-induced liver injury. Given the demonstrated interindividual variation in susceptibility, clinicians should be alert to this potential effect from CBD, which is increasingly available in various nonprescription forms and doses to consumers., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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38. Transdermal Permeation of Caffeine Aided by Ionic Liquids: Potential for Enhanced Treatment of Cellulitis.
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Hernandes AN, Boscariol R, Balcão VM, and Vila MMDC
- Subjects
- Administration, Cutaneous, Adult, Caffeine pharmacokinetics, Cosmetics, Double-Blind Method, Drug Compounding, Drug Stability, Female, Gels, Humans, Ionic Liquids, Middle Aged, Pilot Projects, Skin Absorption, Caffeine administration & dosage, Caffeine therapeutic use, Lipodystrophy drug therapy
- Abstract
Ginoid hydrolipodystrophy (HDLG) or "cellulite" involves alteration of the cutaneous relief and occurs in 80-90% of the female population. Several topical treatments are available with the use of substances capable of stimulating lipolysis, such as caffeine. However, the effectiveness of topical therapy is related to the processes of release and permeation of the active in skin cells. In this sense, ionic liquids, such as choline geranate, are considered to facilitate topical permeation agents. In this way, the aim of this research was to develop and evaluation of the effectiveness of a cosmetic product for topical treatment of cellulite with caffeine in association with choline geranate. The choline geranate was synthesized by the reaction between geranic acid and choline hydroxide [1: 2]. The gel was prepared using 2% Carpobol 940®, 5% caffeine, and 1% choline geranate. Preliminary and accelerated stability tests were performed by checking pH, spreadability, and organoleptic characteristics. The transdermal permeation capacity of caffeine in vitro was evaluated by the Franz cell permeation assay, and the gel cytotoxicity by the MTS method. To prove the efficacy in the treatment of cellulite, a pilot type 1 clinical trial was carried out. The formulation was considered stable and the product maintained your characteristics during 180 days of storage. The product showed moderate cytotoxicity and high skin permeation capacity. In the clinical trial, it showed results superior to the caffeine gel without ionic liquid. The developed gel favored the cutaneous permeation of caffeine, showing a promising product in the treatment of cellulite.
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- 2021
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39. Therapeutic Protein Drug Interaction Potential in Subjects With Psoriasis: An Assessment Based on Population Pharmacokinetic Analyses of Sensitive Cytochrome P450 Probe Substrates.
- Author
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Sathe AG, Othman AA, and Mohamed MF
- Subjects
- Adult, Biological Availability, Caffeine pharmacokinetics, Case-Control Studies, Cytokines metabolism, Drug Interactions, Female, Humans, Male, Midazolam pharmacokinetics, Middle Aged, Patient Acuity, Warfarin pharmacokinetics, Young Adult, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2C9 metabolism, Cytochrome P-450 CYP3A metabolism, Models, Biological, Psoriasis physiopathology
- Abstract
Elevated cytokine levels in inflammatory diseases are associated with downregulation of certain cytochrome P450 (CYP) enzymes. Upon treatment with some cytokine-targeting therapeutic proteins, the CYP enzymes levels may be restored resulting in therapeutic protein-mediated drug interactions (TP-DI). These analyses characterized the worst-case scenario for CYP1A2, 2C9, and 3A-based TP-DI potential in patients with psoriasis by comparing the pharmacokinetics of probe substrates between healthy volunteers and subjects with moderate to severe psoriasis. Data for the CYP probe substrates midazolam (CYP3A), caffeine (CYP1A2), and S-warfarin (CYP2C9) from 7 drug interaction studies (1 in patients with psoriasis and 6 in healthy subjects) were pooled to develop a population pharmacokinetics model for each substrate. A 2-compartment model with absorption lag time for midazolam, a 1-compartment model with 5 transit absorption compartments for caffeine, and a 3-compartment model with absorption lag time for S-warfarin best described the observed data. Apparent oral clearance and relative bioavailability for caffeine and S-warfarin were not significantly different between the subject populations. Psoriasis patients were estimated to have 17% lower midazolam oral bioavailability than healthy volunteers. Compounded with other covariate effects, the ratio of median post hoc area under the plasma concentration-time estimates in subjects with psoriasis relative to healthy subjects was 0.96, 1.13, and 0.65 for midazolam, caffeine, and S-warfarin, respectively. Therefore, inflammation in psoriasis had no relevant effect on reducing CYP1A2, 2C9, and 3A activities in vivo and no significant TP-DIs mediated through these enzymes are expected in patients with psoriasis. This approach can potentially be used in lieu of dedicated TP-DI studies to identify TP-DI risks within a disease area., (© 2020, The American College of Clinical Pharmacology.)
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- 2021
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40. Association Between Maternal Caffeine Consumption and Metabolism and Neonatal Anthropometry: A Secondary Analysis of the NICHD Fetal Growth Studies-Singletons.
- Author
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Gleason JL, Tekola-Ayele F, Sundaram R, Hinkle SN, Vafai Y, Buck Louis GM, Gerlanc N, Amyx M, Bever AM, Smarr MM, Robinson M, Kannan K, and Grantz KL
- Subjects
- Adult, Biomarkers blood, Female, Follow-Up Studies, Gestational Age, Humans, Infant, Newborn, Male, Pregnancy, Retrospective Studies, Theophylline blood, Anthropometry methods, Birth Weight physiology, Caffeine pharmacokinetics, Fetal Development drug effects, Maternal Exposure adverse effects
- Abstract
Importance: Higher caffeine consumption during pregnancy has been associated with lower birth weight. However, associations of caffeine consumption, based on both plasma concentrations of caffeine and its metabolites, and self-reported caffeinated beverage intake, with multiple measures of neonatal anthropometry, have yet to be examined., Objective: To evaluate the association between maternal caffeine intake and neonatal anthropometry, testing effect modification by fast or slow caffeine metabolism genotype., Design, Setting, and Participants: A longitudinal cohort study, the National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, enrolled 2055 nonsmoking women at low risk for fetal growth abnormalities with complete information on caffeine consumption from 12 US clinical sites between 2009 and 2013. Secondary analysis was completed in 2020., Exposures: Caffeine was evaluated by both plasma concentrations of caffeine and paraxanthine and self-reported caffeinated beverage consumption measured/reported at 10-13 weeks gestation. Caffeine metabolism defined as fast or slow using genotype information from the single nucleotide variant rs762551 (CYP1A2*1F)., Main Outcomes and Measures: Neonatal anthropometric measures, including birth weight, length, and head, abdominal, arm, and thigh circumferences, skin fold and fat mass measures. The β coefficients represent the change in neonatal anthropometric measure per SD change in exposure., Results: A total of 2055 participants had a mean (SD) age of 28.3 (5.5) years, mean (SD) body mass index of 23.6 (3.0), and 580 (28.2%) were Hispanic, 562 (27.4%) were White, 518 (25.2%) were Black, and 395 (19.2%) were Asian/Pacific Islander. Delivery occurred at a mean (SD) of 39.2 (1.7) gestational weeks. Compared with the first quartile of plasma caffeine level (≤28 ng/mL), neonates of women in the fourth quartile (>659 ng/mL) had lower birth weight (β = -84.3 g; 95% CI, -145.9 to -22.6 g; P = .04 for trend), length (β = -0.44 cm; 95% CI, -0.78 to -0.12 cm; P = .04 for trend), and head (β = -0.28 cm; 95% CI, -0.47 to -0.09 cm; P < .001 for trend), arm (β = -0.25 cm; 95% CI, -0.41 to -0.09 cm: P = .02 for trend), and thigh (β = -0.29 cm; 95% CI, -0.58 to -0.04 cm; P = .07 for trend) circumference. Similar reductions were observed for paraxanthine quartiles, and for continuous measures of caffeine and paraxanthine concentrations. Compared with women who reported drinking no caffeinated beverages, women who consumed approximately 50 mg per day (~ 1/2 cup of coffee) had neonates with lower birth weight (β = -66 g; 95% CI, -121 to -10 g), smaller arm (β = -0.17 cm; 95% CI, -0.31 to -0.02 cm) and thigh (β = -0.32 cm; 95% CI, -0.55 to -0.09 cm) circumference, and smaller anterior flank skin fold (β = -0.24 mm; 95% CI, -0.47 to -0.01 mm). Results did not differ by fast or slow caffeine metabolism genotype., Conclusions and Relevance: In this cohort study, small reductions in neonatal anthropometric measurements with increasing caffeine consumption were observed. Findings suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine, are associated with decreased fetal growth.
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- 2021
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41. Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea.
- Author
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Faramarzi F, Shiran M, Rafati M, Farhadi R, Salehifar E, and Nakhshab M
- Subjects
- Apnea metabolism, Caffeine administration & dosage, Female, Humans, Infant, Infant, Newborn, Male, Models, Biological, Apnea drug therapy, Caffeine pharmacokinetics, Infant, Premature metabolism
- Abstract
Objectives: Despite extensive caffeine use in preterm infants, the pharmacokinetics (PKs) data are limited because of the studies are complicated to do in these patients. This research was investigated the PK profile of two various dosages of caffeine in premature neonates., Materials and Methods: The PK values of caffeine in premature neonates with Apnea were predicted by using all of computer-based simulation (Simcyp
® ), population-based PK, and modeling (P-Pharm® ). We assayed the plasma levels of caffeine in two groups. The information was analyzed utilizing nonlinear mixed-effects modeling approach. The PK parameters were assessed simulating virtual clinical considers with subjects got 20 mg. kg-1 of caffeine in both groups, which was followed by a 5 mg. kg-1 once daily in Group 1 or 2.5 mg. kg-1 twice daily in Group 2. All statistical analysis was executed utilizing SSPS issue 19 and a P value of 0.05 was chosen significance., Results: In the present study, the means CL, volume of distribution, and T1/2 of caffeine in preterm infants were 0.0476 L. h-1 , 1.1081 L, 16.2284 h, respectively. Whereas our simulated means by Simcyp were 0.090 L. h-1 , 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively., Conclusions: There was overall good agreement between predicted and measured PK values in our study. This study provides an initial demonstration of Simcyp simulation advantage on anticipating of PK parameters., Competing Interests: None- Published
- 2021
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42. Deformable liposomes as enhancer of caffeine penetration through human skin in a Franz diffusion cell test.
- Author
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Abd E, Gomes J, Sales CC, Yousef S, Forouz F, Telaprolu KC, Roberts MS, Grice JE, Lopes PS, Leite-Silva VR, and Andréo-Filho N
- Subjects
- Cells, Cultured, Diffusion, Humans, Caffeine pharmacokinetics, Liposomes, Skin Absorption
- Abstract
Objective: The permeation of hydrophilic molecules through the skin is still a challenge due to the barrier posed by stratum corneum, the outermost layer of the skin. Liposomes have frequently been used as carriers for different types of drugs and may also function as permeation enhancers. Propylene glycol has also been used as an edge activator in liposomes to increase the permeation. The aim of this work was to prepare liposomes containing an edge activator and loaded with caffeine to evaluate the potential of caffeine reaching the deeper layers in the skin., Methods: The formulations were prepared by a top-down process using high-pressure homogenization at 200 00 psi for 10 min. They were characterized by size, polydispersity index (PI), zeta potential (ZP), pH, caffeine content and encapsulation efficiency (EE%) on preparation (time zero) and after 30 days. Cytotoxicity of blank and loaded liposomes was assessed by MTT proliferation assay with a normal keratinocyte cell line (HaCaT). In vitro permeation tests were performed with human skin in Franz cells over 24 h, and caffeine concentration was determined in the skin surface, stratum corneum, dermo-epidermal fraction and receptor medium by HPLC., Results: The caffeine liposomes with (DL-Caf) or without propylene glycol (CL-Caf) showed, respectively, mean size 94.5 and 95.4 nm, PI 0.48 and 0.42, ZP + 1.3 and + 18.1 mV and caffeine content of 78.57 and 80.13%. IC
50 values of caffeine in DL-Caf (3.59 v/v %) and CL-Caf (3.65 v/v %) were not significantly different from conventional blank liposome (3.27 v/v %). The DL-Caf formulation presented the best capability to enhance the caffeine permeation through the skin, resulting 1.94-folds higher than caffeine solution. Furthermore, the caffeine flux from DL-Caf was 1.56- and 3.05-folds higher than caffeine solution and CL-Caf, respectively. On the other hand, CL-Caf showed the lowest caffeine penetration revealing the importance of edge activator to aid hydrophilic drug penetration to all skin layers., Conclusion: The DL-Caf formulation tested was able to improve the permeation of caffeine through the stratum corneum and dermo-epidermal layers, suggesting that this delivery system may be effective for deep skin delivery of hydrophilic drugs., (© 2020 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)- Published
- 2021
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43. PK-DB: pharmacokinetics database for individualized and stratified computational modeling.
- Author
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Grzegorzewski J, Brandhorst J, Green K, Eleftheriadou D, Duport Y, Barthorscht F, Köller A, Ke DYJ, De Angelis S, and König M
- Subjects
- Area Under Curve, Body Weight, Caffeine pharmacokinetics, Clinical Trials as Topic, Contraceptives, Oral administration & dosage, Dose-Response Relationship, Drug, Drug Administration Routes, Drug Administration Schedule, Drug Dosage Calculations, Gene Ontology, Half-Life, Humans, Smoking physiopathology, Databases, Factual, Models, Statistical, Molecular Sequence Annotation, Prescription Drugs pharmacokinetics
- Abstract
A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status, genetic variants); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve) and (iv) measured pharmacokinetic time-courses. Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/PD), or population pharmacokinetic (pop PK) modeling., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
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44. International society of sports nutrition position stand: caffeine and exercise performance.
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Guest NS, VanDusseldorp TA, Nelson MT, Grgic J, Schoenfeld BJ, Jenkins NDM, Arent SM, Antonio J, Stout JR, Trexler ET, Smith-Ryan AE, Goldstein ER, Kalman DS, and Campbell BI
- Subjects
- Anxiety chemically induced, Anxiety genetics, Athletic Performance physiology, Caffeine administration & dosage, Caffeine adverse effects, Caffeine pharmacokinetics, Capsules, Chewing Gum, Cognition drug effects, Cytochrome P-450 CYP1A2 genetics, Cytochrome P-450 CYP1A2 metabolism, Doping in Sports, Drug Dosage Calculations, Energy Drinks, Hot Temperature, Humans, Movement drug effects, Movement physiology, Muscle Strength drug effects, Muscle Strength physiology, Muscle, Skeletal drug effects, Muscle, Skeletal physiology, Performance-Enhancing Substances pharmacology, Physical Endurance drug effects, Physical Endurance physiology, Physical Functional Performance, Receptor, Adenosine A2A genetics, Receptor, Adenosine A2A metabolism, Sleep drug effects, Caffeine pharmacology, Exercise physiology, Societies, Medical, Sports Nutritional Physiological Phenomena, Sports Nutritional Sciences
- Abstract
Following critical evaluation of the available literature to date, The International Society of Sports Nutrition (ISSN) position regarding caffeine intake is as follows: 1. Supplementation with caffeine has been shown to acutely enhance various aspects of exercise performance in many but not all studies. Small to moderate benefits of caffeine use include, but are not limited to: muscular endurance, movement velocity and muscular strength, sprinting, jumping, and throwing performance, as well as a wide range of aerobic and anaerobic sport-specific actions. 2. Aerobic endurance appears to be the form of exercise with the most consistent moderate-to-large benefits from caffeine use, although the magnitude of its effects differs between individuals. 3. Caffeine has consistently been shown to improve exercise performance when consumed in doses of 3-6 mg/kg body mass. Minimal effective doses of caffeine currently remain unclear but they may be as low as 2 mg/kg body mass. Very high doses of caffeine (e.g. 9 mg/kg) are associated with a high incidence of side-effects and do not seem to be required to elicit an ergogenic effect. 4. The most commonly used timing of caffeine supplementation is 60 min pre-exercise. Optimal timing of caffeine ingestion likely depends on the source of caffeine. For example, as compared to caffeine capsules, caffeine chewing gums may require a shorter waiting time from consumption to the start of the exercise session. 5. Caffeine appears to improve physical performance in both trained and untrained individuals. 6. Inter-individual differences in sport and exercise performance as well as adverse effects on sleep or feelings of anxiety following caffeine ingestion may be attributed to genetic variation associated with caffeine metabolism, and physical and psychological response. Other factors such as habitual caffeine intake also may play a role in between-individual response variation. 7. Caffeine has been shown to be ergogenic for cognitive function, including attention and vigilance, in most individuals. 8. Caffeine may improve cognitive and physical performance in some individuals under conditions of sleep deprivation. 9. The use of caffeine in conjunction with endurance exercise in the heat and at altitude is well supported when dosages range from 3 to 6 mg/kg and 4-6 mg/kg, respectively. 10. Alternative sources of caffeine such as caffeinated chewing gum, mouth rinses, energy gels and chews have been shown to improve performance, primarily in aerobic exercise. 11. Energy drinks and pre-workout supplements containing caffeine have been demonstrated to enhance both anaerobic and aerobic performance.
- Published
- 2021
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45. Pharmacokinetic Variability of Caffeine in Routinely Treated Preterm Infants: Preliminary Considerations on Developmental Changes of Systemic Clearance.
- Author
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Taguchi M, Kawasaki Y, Katsuma A, Mito A, Tamura K, Makimoto M, and Yoshida T
- Subjects
- Age Factors, Body Surface Area, Caffeine blood, Caffeine therapeutic use, Chromatography, Liquid, Female, Humans, Inactivation, Metabolic, Infant, Infant, Newborn, Liver metabolism, Male, Tandem Mass Spectrometry, Caffeine pharmacokinetics, Infant, Premature blood
- Abstract
The purpose of this study was to clarify the variability of serum concentrations of caffeine (CAF) in preterm infants, and to deliberate on a better explanation for developmental changes of systemic clearance during the neonatal period. Forty-nine serum samples were obtained from 23 preterm neonates (age, 34.1 ± 18.8 d), and additive blood sampling was conducted periodically for 10 of the 23 patients after discontinuation of CAF treatment. The concentrations of CAF and its major metabolites were determined by liquid chromatography-tandem mass spectrometory. The serum concentrations of CAF were within therapeutic levels (5-25 µg/mL) in 37 samples and exceeded 25 µg/mL in the rest of the 12 samples, although no sample was in the toxic range (> 50 µg/mL). The inter- and intra-individual variability of the concentration to dose (C/D) ratio corrected for body surface area (BSA) was more negatively associated with postmenstrual age (PMA) rather than postnatal age (PNA). The serum concentrations of major metabolites were much smaller than those of CAF throughout the study, suggesting that the contribution of hepatic metabolism to drug elimination was small in the preterm infants under 241 d of PMA. The mean values for elimination half-life and oral clearance estimated in the 10 patients were 124.6 ± 44.6 h and 2.26 ± 0.73 mL/min/1.73 m
2 , respectively. Consequently, we confirmed that the exposure to CAF was considerably variable and provided additive insight that the C/D ratio corrected for patient's BSA and PMA are promising for describing and understanding the developmental change of clearance in preterm infants.- Published
- 2021
- Full Text
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46. Comparison of Membrane Depth Determination Techniques for Active Ingredient Skin Penetration Studies Using Microdialysis.
- Author
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Lubda M, Zander M, Salazar A, Kolmar H, and von Hagen J
- Subjects
- Animals, Hydrophobic and Hydrophilic Interactions, Swine, Caffeine pharmacokinetics, Epidermis metabolism, Microdialysis methods, Skin Absorption physiology
- Abstract
Introduction: The skin is a major physical barrier to the environment, and thus, percutaneous delivery of active ingredients to the dermal target site faces a unique set of hurdles. The efficacy of these active ingredients is governed by their release into the underlying epidermal and dermal tissue, especially when administered topically., Objective: The aim of this study was to understand if different physicochemical properties influence the skin penetration of active ingredients and the depth to which they penetrate into the dermis., Methods: A microdialysis (MD) setup was used to compare the percutaneous penetration in superficial and deep implanted MD membranes in porcine skin. The precise MD membrane depth was determined using histological sectioning paired with microscopy, ultrasound, and a novel computed tomographic approach., Results: In study A, the measured depth of the superficial and deep implanted MD membranes was compared using histological sectioning, ultrasound, and computed tomography. Experimental determination of the depth up to which penetration occurs was found to be crucial to percutaneous penetration studies. In study B, the lipophilic differences of the active ingredients and its influences on the penetration was tested using hydrophilic caffeine and lipophilic LIP1 as model compounds, which have an identical molecular weight with different lipophilic characteristics. It is assumed that the lipophilic characteristics of active ingredients influence their penetration and thus governs the concentration of these molecules reaching their target site., Conclusion: The transdermal penetration of caffeine was found to exceed that of LIP1 through the hydrophilic environment of the dermis. Thus, the findings of this study show that the precise MD dermis localization and the physicochemical properties, such as lipophilicity, influence the penetration rate of active ingredients and lay the foundation for creating optimized transdermal delivery systems., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
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47. Massive β1-Adrenergic Receptor Reaction Explains Irreversible Acute Arrhythmia in a Fatal Case of Acute Pure Caffeine Intoxication.
- Author
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Maiese A, La Russa R, Del Fante Z, Turillazzi E, David MC, Frati P, and Fineschi V
- Subjects
- Adult, Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Caffeine pharmacokinetics, Central Nervous System Stimulants pharmacokinetics, Epinephrine urine, Fatal Outcome, Female, Humans, Norepinephrine urine, Arrhythmias, Cardiac chemically induced, Caffeine poisoning, Central Nervous System Stimulants poisoning, Heart Rate drug effects, Receptors, Adrenergic, beta-1 metabolism
- Abstract
Caffeine, a naturally occurring purine-based alkaloid, is the most consumed psychostimulant worldwide. Since caffeine pharmacokinetics shows extreme interindividual variability, it is not easy to establish its toxic dose. Only a few cases of death due to acute caffeine intoxication have been described so far, the majority of which attributable to massive assumption of caffeine-based medications. We present a case of acute caffeine overdose due to ingestion of pure caffeine. The extremely high blood concentration of caffeine determined a strong cardiovascular response, leading to fatal arrhythmia, as supported by histological evidence of myocardial injury. Quantitation of catecholamines and their metabolites in urine samples was performed and showed level near the highest limit of normal ranges for norepinephrine and high level of epinephrine. Contraction band is a pathological modification of the myocell caused by the catecholaminergic action and can occur in conditions of alteration due to the interaction between calcium and catecholamines. We demonstrated the β1-adrenoceptor involvement in our fatal case by immunohistochemical analysis.
- Published
- 2021
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48. Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities.
- Author
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Miura M, Tanaka S, Uchida S, Kamiya C, Katayama N, Hakamata A, Odagiri K, Inui N, Kawakami J, Watanabe H, and Namiki N
- Subjects
- Administration, Oral, Adult, Caffeine blood, Caffeine pharmacokinetics, Dextromethorphan blood, Dextromethorphan pharmacokinetics, Humans, Losartan blood, Losartan pharmacokinetics, Male, Midazolam blood, Midazolam pharmacokinetics, Omeprazole blood, Omeprazole pharmacokinetics, Young Adult, Area Under Curve, Cytochrome P-450 Enzyme System metabolism, Models, Biological
- Abstract
A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.
- Published
- 2021
- Full Text
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49. Population pharmacokinetic study of caffeine citrate in Chinese premature infants with apnea.
- Author
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Guo A, Zhu Z, Xue J, Di X, Fan J, Huang L, Zhao P, Hu X, and Xie H
- Subjects
- Asian People, Caffeine administration & dosage, Central Nervous System Stimulants administration & dosage, Citrates administration & dosage, Female, Humans, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases drug therapy, Male, Nonlinear Dynamics, Retrospective Studies, Apnea drug therapy, Caffeine pharmacokinetics, Central Nervous System Stimulants pharmacokinetics, Citrates pharmacokinetics, Models, Biological
- Abstract
What Is Known and Objectives: Caffeine citrate is a commonly used methylxanthine for pharmacologic treatment of apnea of prematurity. The aim of this study was to develop and verify a population pharmacokinetic (PPK) model, which can provide a reference for individualized caffeine citrate treatment of apnea in Chinese premature infants., Methods: A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29 weeks) were retrospectively collected and the relevant clinical data of patients were recorded. The PPK analysis was performed by non-linear mixed-effect modelling method using NONMEM. Allometric scaling was applied in the PPK analysis, and the final model was evaluated by graphic and statistical methods, including goodness-of-fit plots, normalized prediction distribution errors plots and bootstrap procedures., Results: A one-compartment model with first-order elimination was successfully fitted to the data. The typical scaled values for the parameters clearance and volume of distribution (V) were 0.268 L/h and 109 L per 70 kg, respectively. The weight at the time of blood collection (CW) and post-natal age were identified as important predictors for pharmacokinetic parameters of caffeine. The evaluation process showed good stability and predictability of the final PPK model., What Is New and Conclusion: This is a complete PPK study of caffeine citrate in Chinese premature infants with apnea, which complements caffeine pharmacokinetic data of the premature from China. A final PPK model was developed which may serve as a beneficial tool for the use of caffeine citrate in the treatment of apnea in Chinese preterm infants., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
50. Effect of High-Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long-lasting Inhibition of CYP2C19.
- Author
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Kaartinen TJK, Tornio A, Tapaninen T, Launiainen T, Isoherranen N, Niemi M, and Backman JT
- Subjects
- Administration, Oral, Caffeine pharmacokinetics, Cross-Over Studies, Cytochrome P-450 CYP1A2 Inducers pharmacology, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2C19 Inhibitors administration & dosage, Cytochrome P-450 CYP2C19 Inhibitors pharmacokinetics, Cytochrome P-450 CYP3A Inhibitors pharmacology, Esomeprazole administration & dosage, Esomeprazole pharmacokinetics, Female, Healthy Volunteers, Humans, Male, Midazolam pharmacokinetics, Models, Biological, Pantoprazole pharmacokinetics, Pharmacogenomic Variants, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2C19 metabolism, Cytochrome P-450 CYP2C19 Inhibitors pharmacology, Cytochrome P-450 CYP3A metabolism, Esomeprazole pharmacology
- Abstract
In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half-life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in ~ 3-4 days after discontinuation of esomeprazole treatment., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
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