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Purpose: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). Methods: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. Results: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). Conclusions: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies. [ABSTRACT FROM AUTHOR]

Background: Intramuscular (L-)epinephrine is used as self-medication for serious hypersensitivity reactions. Inhalative administration has the theoretical advantage of a more rapid absorption and better controllability. Objectives: The current trial was conducted to explore pharmacokinetics and pharmacodynamics of two nebulized inhalative epinephrine doses (4 mg and 8 mg in aqueous solution) using a mobile pocket inhaler relative to intramuscular administration (0.3 mg) and placebo. Methods: This randomized, open-label, change-over pilot study involved eight young healthy men and women. Noncompartmental pharmacokinetic and pharmacodynamic parameters were calculated from epinephrine plasma concentrations and hemodynamic parameters. Results: Mean exposure to epinephrine decreased from the 8 mg dose to the 4 mg inhalative dose, and further with the 0.3 mg intramuscular dose, with active treatments showing significantly higher concentrations than placebo (geometric mean area under the curve AUC values: 282, 236, 204 and 81.6 hr*ng/L). Maximal concentrations were reached within approximately 15 min for all active treatments. Epinephrine effects for inhalative administrations on heart rates were significantly higher than those for the intramuscular or placebo administration, while no excessive effects occurred. Pronounced overall variability prohibited a definite assessment of relative bioavailability between treatments. However, results indicated that epinephrine concentrations obtained following the 8 mg inhalative dose were not inferior to those after 0.3 mg i.m. Conclusions: A relevant fraction of moist inhalation epinephrine doses is absorbed and mediates systemic effects. This suggests that administration of epinephrine via a suitable pocket inhaler device may be beneficial in ambulatory emergency treatment of systemic hypersensitivity reactions. EudraCT number: 2010-021493-11 [ABSTRACT FROM AUTHOR]

Objectives: To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. Methods: Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. Results: A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8-60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646-2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). Conclusion: We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761® with respect to the activities of major cytochrome P450 (CYP) enzymes. Methods: A single-center, open-label, randomized, three-fold crossover, cocktail phenotyping design was applied. In random order, the following treatments were administered to 18 healthy men and women for 8 days each: placebo twice daily, EGb 761® 120 mg twice daily, and EGb 761® 240 mg in the morning and placebo in the evening. In the morning of day 8, administration was performed together with the orally administered phenotyping cocktail (enzyme, metric): 150 mg caffeine (CYP1A2, paraxanthine/caffeine plasma ratio 6-h postdose), 125 mg tolbutamide (CYP2C9, plasma concentration 24-h postdose), 20 mg omeprazole (CYP2C19, omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose), 30 mg dextromethorphan (CYP2D6, dextromethorphan/dextrorphan plasma ratio 3-h postdose), and 2 mg of midazolam (CYP3A, plasma concentration 6-h postdose). Formally, absence of a relevant interaction was assumed if the 90% confidence intervals (CIs) for EGb 761®/placebo ratios of the metrics were within the 0.70-1.43 range. Results: EGb 761®/placebo ratios for phenotyping metrics were close to unity for all CYPs. Furthermore, respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761® 120 mg twice daily (90% CI 0.681-1.122) and for CYP2D6 for EGb 761® 240 mg once daily (90% CI 0.667-1.281). These findings were attributed to the intraindividual variability of the metrics used. All treatments were well tolerated. Conclusion: EGb 761® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug-drug interactions. [ABSTRACT FROM AUTHOR]

The 4-anilinoquinazolines (gefitinib, erlotinib and lapatinib) are members of a class of potent and selective inhibitors of the human epidermal growth factor receptor (HER) family of tyrosine kinases that have been developed to treat patients with tumours with defined genetic alterations of the HER tyrosine kinase domain. They are characterized by a moderate rate of absorption after oral administration with peak plasma concentrations at several hours post-dose. Absolute bioavailability of gefitinib and erlotinib is about 60%. Low bioavailability is assumed for lapatinib. The drugs are extensively distributed in human tissues, including tumour tissues, have a large volume of distribution at least 3-fold exceeding the volume of body water and are extensively (about 95%) protein bound to α(1)-acid glycoprotein and albumin. Existing human data for gefitinib and erlotinib indicate that these substances penetrate into the central nervous system and accumulate in brain tumours, possibly due to leaks in the blood-brain barrier. Gefitinib, erlotinib and the absorbed fraction of lapatinib undergo extensive metabolism - mainly via hepatic and intestinal cytochrome P450 (CYP) 3A4 and also via CYP2D6 (gefitinib) and CYP1A2 (erlotinib) - and are primarily eliminated by biotransformation. The excretion of unchanged gefitinib, erlotinib, lapatinib and their metabolites occurs predominantly in the faeces and only a minor fraction is excreted in the urine. No relevant effects of age, sex, bodyweight or race on their pharmacokinetics have been reported to date. Limited available data indicate that genetic polymorphisms in enzymes and transporters involved in the pharmacokinetics of gefitinib (CYP2D6) and erlotinib (CYP3A4, CYP3A5 and ABCG2 [breast cancer resistance protein]) alter the exposure to these drugs. Modification of drug dose should be considered in patients with severe hepatic impairment receiving these tyrosine kinase inhibitors and in current smokers receiving erlotinib. Existing recommendations for dose adjustment (i.e. a dose decrement or increment for gefitinib, erlotinib and lapatinib in the presence of CYP3A4 inhibitors or inducers, respectively; a dose increase for erlotinib in smoking patients) need to be validated in clinical studies. Further investigations are required to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess the clinical relevance of interaction potential and inhibitory effects on the metabolizing enzymes and transporters. [ABSTRACT FROM AUTHOR]

Comparative potency of proton-pump inhibitors (PPIs) is an important clinical issue. Most available trials have compared the different PPIs at one or a few selected specific dosages, making it difficult to derive quantitative equivalence dosages. Here we derived PPI dose equivalents based on a comprehensive assessment of dose-dependent effects on intragastric pH. All available clinical studies reporting the effects of PPIs on mean 24-h intragastric pH were sought from electronic databases including Medline. Studies included were restricted to those targeting the Caucasian population, and healthy volunteers or gastroesophageal reflux disease (GERD) patients. The dose-effect relationships for mean 24-h intragastric pH and for percentage of time with pH > 4 in 24 h were analyzed for each PPI using pharmacodynamic modeling with NONMEM and a model integrating all available data. Fifty-seven studies fulfilled the inclusion criteria. Based on the mean 24-h gastric pH, the relative potencies of the five PPIs compared to omeprazole were 0.23, 0.90, 1.00, 1.60, and 1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, respectively. Compared with healthy volunteers, patients with GERD needed a 1.9-fold higher dose and Helicobacter pylori-positive individuals needed only about 20% of the dose to achieve a given increase in mean 24-h intragastric pH. The present meta-analysis provides quantitative estimates on clinical potency of individual PPIs that may be helpful when switching between PPIs and for assessing the cost-effectiveness of specific PPIs. However, our estimates must be viewed with caution because only a limited dose range has been tested and not exactly the same study conditions were applied for the different substances. [ABSTRACT FROM AUTHOR]

Coumarin derivatives, including warfarin, acenocoumarol and phenprocoumon, are the drugs of choice for long-term treatment and prevention of thromboembolic events. The management of oral anticoagulation is challenging because of a large variability in the dose-response relationship, which is in part caused by genetic polymorphisms. The narrow therapeutic range may result in bleeding complications or recurrent thrombosis, especially during the initial phase of treatment. The aim of this review is to systematically extract the published data reporting pharmacogenetic influences on oral anticoagulant therapy and to provide empirical doses for individual genotype combinations. To this end, we extracted all data from clinical studies of warfarin, phenprocoumon and acenocoumarol that reported genetic influences on either the dose demand or adverse drug effects, such as bleeding complications. Data were summarized for each substance, and the relative effect of each relevant gene was calculated across studies, assuming a linear gene-dose effect in Caucasians. Cytochrome P450 (CYP) 2C9, which is the main enzyme for rate-limiting metabolism of oral anticoagulants, had the largest impact on the dose demand. Compared with homozygous carriers of CYP2C9*1, patients homozygous for CYP2C9*3 were estimated to need 3.3-fold lower mean doses of warfarin to achieve the same international normalized ratio, with *2 carriers and heterozygous patients in between. Differences for acenocoumarol and phenprocoumon were 2.5-fold and 1.5-fold, respectively. Homozygosity of the vitamin K epoxide reductase complex subunit 1 (VKORC1) variant C1173T (*2) allele (VKORC1 is the molecular target of anticoagulant action) was related to 2.4-fold, 1.6-fold and 1.9-fold lower dose requirements compared with the wild-type for warfarin, acenocoumarol and phenprocoumon, respectively. Compared with CYP2C9 and VKORC1 homozygous wild-type individuals, patients with polymorphisms in these genes also more often experience severe overanticoagulation. An empirical dose table, which may be useful as a basis for dose individualization, is presented for the combined CYP2C9/VKORC1 genotypes. Genetic polymorphism in further enzymes and structures involved in the effect of anticoagulants such as gamma-glutamylcarboxylase, glutathione S-transferase A1, microsomal epoxide hydrolase and apolipoprotein E appear to be of negligible importance.Despite the clear effects of CYP2C9 and VKORC1 variants, these polymorphisms explain less than half of the interindividual variability in the dose response to oral anticoagulants. Thus, while individuals at the extremes of the dose requirements are likely to benefit, the overall clinical merits of a genotype-adapted anticoagulant treatment regimen in the entire patient populations remain to be determined in further prospective clinical studies. [ABSTRACT FROM AUTHOR]

Approximately one in 200 hospitalised patients has a serious adverse drug effect caused by drug-drug interactions (DDIs). Such adverse effects should be avoidable, but current information provided on DDIs is often incomplete and difficult or even impossible to translate into true risk and appropriate tangible action. Clinicians need to know the mean and maximal expected effect of a DDI on clinical endpoints, any dose adjustments required, and how to monitor tolerability and efficacy in patients subject to a DDI. To this end, improved study designs should take the objective of improving treatment explicitly into account, and any existing DDI data should be publicly accessible. Modelling needs to be used more extensively in order to quantitatively predict the effects of DDIs on clinical endpoints in patients and to relate clinical endpoint effects considered as acceptable to respective changes in experimental and clinical studies. Computer-based expert systems will be required to convert such DDI data into recommendations applicable to the individual patient. Therefore, the incorporation of DDIs in a more general procedure for personalisation of drug therapy is desirable. [ABSTRACT FROM AUTHOR]

For most drug-metabolizing enzymes (DMEs), the functional consequences of genetic polymorphisms have been examined. Variants leading to reduced or increased enzymatic activity as compared to the wild-type alleles have been identified. This review tries to define potential fields in the therapy of major medical conditions where genotyping (or phenotyping) of genetically polymorphic DMEs might be beneficial for drug safety or therapeutic outcome. The possible application of genotyping is discussed for depression, cardiovascular diseases and thromboembolic disorders, gastric ulcer, malignant diseases and tuberculosis. Some drugs used for relief of these ailments are metabolized with participation of genetically polymorphic DMEs including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase and N-acetyltransferase type 2. Current evidence suggests that taking genetically determined metabolic capacities of DMEs into account has the potential to improve individual risk/benefit relationship. However, more prospective studies with clinical endpoints are needed before the paradigm of ‘personalized medicine’ based on DME variants can be established.The Pharmacogenomics Journal (2008) 8, 4–15; doi:10.1038/sj.tpj.6500462; published online 5 June 2007 [ABSTRACT FROM AUTHOR]

Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes catalyzing biotransformation of xenobiotics in the human liver. This enzyme’s activity shows a high degree of interindividual variability caused in part by its genetic polymorphism, the so-called debrisoquine/sparteine polymorphism. The genetic component influencing CYP2D6 activity can be determined by genotyping. However, genotyping alone is not sufficient to accurately predict an individual’s actual CYP2D6 activity, as this is also influenced by other factors. For the determination of the exact actual enzymatic activity (“phenotyping”), adequate probe drugs have to be administered prior to measurements of these compounds and/or their metabolites in body fluids. Debrisoquine, sparteine, metoprolol or dextromethorphan represent well-established probe drugs while tramadol has been recently investigated for this purpose. The enzymatic activity is reflected by various pharmacokinetic metrics such as the partial clearance of a parent compound to the respective CYP2D6-mediated metabolite or metabolic ratios. Appropriate metrics need to fulfill pre-defined validation criteria. In this review, we have compiled a list of such criteria useful to select the best metrics to reflect CYP2D6 activity. A comprehensive Medline search for reports on CYP2D6 phenotyping trials with the above mentioned probe drugs was carried out. Application of the validation criteria suggests that dextromethorphan and debrisoquine are the best CYP2D6 phenotyping drugs, with debrisoquine having the problem of very limited availability as a therapeutic drug. However, the assessment of the best dextromethorphan CYP2D6 phenotyping metric/procedure is still ongoing. [ABSTRACT FROM AUTHOR]

Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21–46 years; 31 men, six women) were assigned to one of the following groups: (1) absence of GS (non-GS)/rapid acetylator (RA) (N=11); (2) GS/RA (N=8); (3) non-GS/SA (N=11); (4) GS/SA (N=7). Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple-dose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9–172.5) relative to SA subjects (P=0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.The Pharmacogenomics Journal (2006) 6, 211–219. doi:10.1038/sj.tpj.6500359; published online 10 January 2006 [ABSTRACT FROM AUTHOR]

Objective: Permethrin is an insecticide used in the treatment of lice and scabies infections. Although its efficacy and safety have been well documented, pharmacokinetic data are sparse. The objective of this study was to determine the systemic exposure of permethrin and the duration of residence in the human body following topical administration. Methods: The study consisted of three parts. In six young healthy men (part 1), 50 ml of an ethanolic solution containing 215 mg permethrin (cis/trans: 25/75) was administered to the hair of the head. In another six young healthy men (part 2) and in six male or female scabies patients (part 3), 60 g of cream containing 3 g permethrin was administered to the skin of the whole body. Urine was collected up to 168 h post-dose. Urinary excretion of the main metabolite of permethrin, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid, and its conjugates was measured using a gas chromatography/electron capture detection method. Results: Pharmacokinetics were similar in all study parts. The time of maximal urinary excretion rate was 12.3, 20.0 and 14.6 h, terminal elimination half-life was 32.7, 28.8 and 37.8 h and urinary recovery of the metabolite reached 0.35, 0.47 and 0.52 M percent of the permethrin dose, respectively, in parts 1, 2 and 3 (means). The treatment was well tolerated. Conclusions: The extent of systemic exposure following external therapeutic administration of permethrin is very low compared with doses used for preclinical toxicity studies, and elimination is virtually complete after 1 week. These data provide the pharmacokinetic basis for the clinical safety of topical permethrin. [ABSTRACT FROM AUTHOR]

Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a ‘Pharmacogenomics Education Forum’ was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of ‘Background Statement’ and ‘Recommendations and Call for Action’ addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.The Pharmacogenomics Journal (2005) 5, 221–225. doi:10.1038/sj.tpj.6500312; published online 26 April 2005 [ABSTRACT FROM AUTHOR]

Currently, 5 different main mechanisms of induction are distinguished for drug-metabolising enzymes. The ethanol type of induction is mediated by ligand stabilisation of the enzyme, but the others appear to be mediated by intracellular 'receptors'. These are the aryl hydrocarbon (Ah) receptor, the peroxisome proliferator activated receptor (PPAR), the constitutive androstane receptor (CAR, phenobarbital induction) and the pregnane X receptor [PXR, rifampicin (rifampin) induction]. Enzyme induction has the net effect of increasing protein levels. However, many inducers are also inhibitors of the enzymes they induce, and the inductive effects of a single drug may be mediated by more than one mechanism. Therefore, it appears that every inducer has its own pattern of induction; knowledge of the main mechanism is often not sufficient to predict the extent and time course of induction, but may serve to make the clinician aware of potential dangers. The possible pharmacokinetic consequences of enzyme induction depend on the localisation of the enzyme. They include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance or accelerated formation of reactive metabolites, which is usually related to local toxicity. Although some severe drug-drug interactions are caused by enzyme induction, most of the effects of inducers are not detected in the background of nonspecific variation. For any potent inducer, however, its addition to, or withdrawal from, an existing drug regimen may cause pronounced concentration changes and should be done gradually and with appropriate monitoring of therapeutic efficacy and adverse events. The toxicological consequences of enzyme induction in humans are rare, and appear to be mainly limited to hepatoxicity in ethanol-type induction. [ABSTRACT FROM AUTHOR]

Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (C) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interaction are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for that drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the absorption of nifedipine in man from four different sites of the gastrointestinal tract. Methods: On separate occasions, nifedipine solution was administered locally to the stomach, the small intestine and two sites in the colon in 4 healthy male volunteers (age 29-34 y weight 73-82 kg, non-smokers) using a remote controlled drug delivery device (HF-capsule). In order to assess absolute and relative bioavailabilities, an intravenous infusion was given on a separate occasion and all treatments were accompanied by a simultaneous oral dose of a stable-isotope labelled nifedipine solution. This allowed to minimise the influence of intra-individual variability. Plasma samples were collected up to 24 h post dose and faeces for 72 h. A new method of analysis of nifedipine in plasma and faeces using gas chromatography with mass-selective detection (GCMS) was employed. Results: Dissolved nifedipine was found to enter the systemic circulation completely along the intestine, being absorbed from jejunum to colon. Absorption was less rapid from the colon than from the upper part of the gut, but this was not associated with a decrease in absorption and/or bioavailability: Absolute bioavailability, calculated from the normalised AUC values, ranged from 42 to 56%, and bioavailability relative to oral solution was 100 to 126% (medians of the application sites). Conclusion: The absence of an absorption window in the intestinal tract suggests that nifedipine is well suited for use in controlled-release formulations. [ABSTRACT FROM AUTHOR]

The cardiovascular effects at rest and during exercise and β- and β-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p. o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p. o., using a place-bo-controlled, 2-way cross-over design. The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median β-RRA and β-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to β-adrenoceptors, moderately to β-adrenoceptors, acts as β-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect β-adrenergic agonism, but which might reflect β-adrenergic agonism. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the role of CYP3A5 polymorphisms in the pharmacokinetics and pharmacodynamics of the CYP3A probe drugs alfentanil and midazolam, both CYP3A4 and CYP3A5 substrates.

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