112 results on '"Norcodeine"'
Search Results
2. Breaking the Codeine : Fatal Forty DDI: codeine, quinidine, CYP2D6
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Christensen, Clint, Orgain, Nathan G., Dull, Randal O., Marcucci, Catherine, editor, Hutchens, Michael P., editor, Wittwer, Erica D., editor, Weingarten, Toby N., editor, Sprung, Juraj, editor, Nicholson, Wayne T., editor, Lalwani, Kirk, editor, Metro, David G., editor, Dull, Randal O., editor, Swide, Christopher E., editor, Seagull, F. Jacob, editor, Kirsch, Jeffrey R., editor, and Sandson, Neil B., editor
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- 2015
- Full Text
- View/download PDF
3. Codeine Can’t Do It : Fatal Forty DDI: codeine, fluoxetine, CYP2D6
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Bojanić, Katarina, Nicholson, Wayne T., Wittwer, Erica D., Weingarten, Toby N., Sprung, Juraj, Marcucci, Catherine, editor, Hutchens, Michael P., editor, Wittwer, Erica D., editor, Weingarten, Toby N., editor, Sprung, Juraj, editor, Nicholson, Wayne T., editor, Lalwani, Kirk, editor, Metro, David G., editor, Dull, Randal O., editor, Swide, Christopher E., editor, Seagull, F. Jacob, editor, Kirsch, Jeffrey R., editor, and Sandson, Neil B., editor
- Published
- 2015
- Full Text
- View/download PDF
4. Metabolism, pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses
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Heather K Knych, D. S. Mckemie, Philip H. Kass, Carrie J. Finno, and Sophie R. Gretler
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Oral ,Male ,040301 veterinary sciences ,Metabolite ,Cmax ,Administration, Oral ,Pharmacology ,Drug Administration Schedule ,Article ,0403 veterinary science ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Norcodeine ,Pharmacokinetics ,030202 anesthesiology ,Oral administration ,pharmacodynamics ,Animals ,Medicine ,Veterinary Sciences ,Horses ,Active metabolite ,General Veterinary ,Codeine ,business.industry ,04 agricultural and veterinary sciences ,horse ,chemistry ,Area Under Curve ,Anesthesia ,Administration ,Morphine ,Female ,business ,metabolism ,pharmacokinetics ,Half-Life ,medicine.drug - Abstract
OBJECTIVE: To describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 12 Thoroughbred horses, nine geldings and three mares, aged 4–8 years. METHODS: Horses were administered codeine (0.6 mg kg(−1)) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration. RESULTS: Codeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The C(max,) t(max) and elimination t(½) were 270.7 ± 136.0 ng mL(−1), 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (C(max) 492.7 ± 35.5 ng mL(−1)), followed by C6G (C(max) 96.1 ± 33.8 ng mL(−1)) and M6G (C(max) 22.3 ± 4.96 ng mL(−1)). Morphine and norcodeine were the least abundant metabolites with C(max) of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL(−1), respectively. No significant adverse or excitatory effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Following oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.
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- 2020
5. Characterization of the in vitro CYP450 mediated metabolism of the polymorphic CYP2D6 probe drug codeine in horses
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D. S. Mckemie, Sophie R. Gretler, Russell Baden, and Heather K Knych
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0301 basic medicine ,Metabolite ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Norcodeine ,Pharmacokinetics ,Tandem Mass Spectrometry ,medicine ,Animals ,Cytochrome P-450 CYP3A ,Horses ,Biotransformation ,Cells, Cultured ,Morphine ,biology ,Codeine ,Chemistry ,Cytochrome P450 ,Recombinant Proteins ,030104 developmental biology ,Cytochrome P-450 CYP2D6 ,030220 oncology & carcinogenesis ,Microsomes, Liver ,biology.protein ,Female ,Glucuronide ,Drug metabolism ,Chromatography, Liquid ,medicine.drug - Abstract
Despite their widespread popularity as sport and companion animals and published and anecdotal reports of vast difference in drug disposition and pharmacokinetics between individuals, studies describing equine drug metabolism are limited. It has been theorized that similar to humans, members of the CYP2D family in horses may be polymorphic in nature leading to differences in metabolism of substrates. This study aims to build on the limited current knowledge regarding P450 mediated metabolism in horses by describing the metabolism of the polymorphic CYP2D6 probe drug codeine in vitro. Codeine, at varying substrate concentrations, was incubated with equine liver microsomes (±UDPGA) and a panel of baculovirus expressed recombinant equine P450s. Parent drug and metabolite concentrations were determined using LC-MS/MS. Incubation of codeine in equine liver microsomes generated norcodeine, morphine, codeine glucuronide and morphine 3- and 6- glucuronide. In recombinant P450 assays, the newly described CYP2D82 was responsible for catalyzing the biotransformation of codeine to morphine (Km of 247.4 μM and a Vmax of 1.6 pmol/min/pmol P450). CYP2D82 is 80% homologous to the highly polymorphic CYP2D6 enzyme, which is responsible for biotransformation of codeine to morphine in humans. CYP3A95, which shares 79% sequence homology with human CYP3A4 and CYP2D50 catalyzed the conversion of codeine to norcodeine (Km of 104.1 and 526.9 μM, Vmax of 2.8 and 2.6 pmol/min/pmol P450). In addition to describing the P450 mediated metabolism of codeine, the current study offers a candidate probe drug that could be used in vivo to study the functional implications of polymorphisms in the CYP2D gene in horses.
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- 2019
6. Heroin-Related Compounds and Metabolic Ratios in Postmortem Samples Using LC-MS-MS
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Henrik Gréen, Robert Kronstrand, Gerd Jakobsson, Michael T. Truver, and Sonja A Wrobel
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AcademicSubjects/SCI01040 ,Health, Toxicology and Mutagenesis ,AcademicSubjects/SCI00030 ,Physiology ,Urine ,Pharmacology and Toxicology ,Toxicology ,01 natural sciences ,Article ,Analytical Chemistry ,Heroin ,03 medical and health sciences ,0302 clinical medicine ,Norcodeine ,Tandem Mass Spectrometry ,medicine ,Environmental Chemistry ,030216 legal & forensic medicine ,Normorphine ,Morphine Derivatives ,Chemical Health and Safety ,Morphine ,AcademicSubjects/MED00305 ,business.industry ,Codeine ,010401 analytical chemistry ,Ethylmorphine ,Farmakologi och toxikologi ,0104 chemical sciences ,Analgesics, Opioid ,Substance Abuse Detection ,Opiate ,business ,medicine.drug ,Chromatography, Liquid - Abstract
Analysis of postmortem samples with the presence of morphine can sometimes be challenging to interpret. Tolerance complicates interpretation of intoxications and causes of death due to overlap in therapeutic and fatal concentrations. Determination of metabolites and metabolic ratios can potentially differentiate between abstinence, continuous administration, and perhaps time of administration. The purpose of this study was to (a) develop and validate a method for quantitation of morphine-3β-D-glucuronide, morphine-6β-D-glucuronide, normorphine, codeine-6β-D-glucuronide, norcodeine, codeine, 6-acetylmorphine, and ethylmorphine in urine using liquid chromatography–tandem mass spectrometry; (b) apply the method to opiate related deaths; (c) compare metabolic ratios in urine in different causes of death (CoD) and after different drug intakes and (d) compare heroin intoxications in rapid and delayed deaths. Validation parameters such as precision, bias, matrix effects, stability, process efficiency, and dilution integrity were assessed and deemed acceptable. Lower limits of quantitation ranged from 0.01–0.2 μg/mL for all analytes. Autopsy cases (n=135) with paired blood and urine samples were analyzed. Cases were divided into three groups based on CoD; opiate intoxication, intoxication with other drugs than opiates, and other CoD. The cases were classified by intake: codeine (n=42), heroin (n=36), morphine (n=49), and ethylmorphine (n=3). Five cases were classified as mixed intakes and excluded. Heroin intoxications (n=35) were divided into rapid (n=15) or delayed (n=20) deaths. Parent drug groups were compared using metabolic ratio morphine-3β-D-glucuronide/morphine and significant differences were observed between codeine vs morphine (p=0.005) and codeine vs heroin (p≤0.0001). Urine and blood concentrations, and metabolic ratios in rapid and delayed heroin intoxications were compared and determined a significant difference for morphine (p=0.001), codeine (p=0.009), 6-acetylmorphine (p=0.02) in urine, and morphine (p=0.02) in blood, but there was no significant difference (p=0.9) between metabolic ratios. Morphine-3β-D-glucuronide results suggested a period of abstinence prior to death in 25% of the heroin intoxications.
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- 2021
7. Drugs in Hair. Part I. Metabolisms of Major Drug Classes.
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White, R. M.
- Abstract
Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered. [ABSTRACT FROM AUTHOR]
- Published
- 2017
8. Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme
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Linda Gatchie, Ibidapo S. Williams, Bhabatosh Chaudhuri, and Sandip B. Bharate
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0301 basic medicine ,CYP2D6 ,General Chemical Engineering ,digestive system ,030226 pharmacology & pharmacy ,law.invention ,lcsh:Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Norcodeine ,law ,medicine ,skin and connective tissue diseases ,chemistry.chemical_classification ,biology ,Cytochrome P450 ,General Chemistry ,Yeast ,030104 developmental biology ,Enzyme ,lcsh:QD1-999 ,chemistry ,Biochemistry ,Morphine ,biology.protein ,Recombinant DNA ,Drug metabolism ,medicine.drug - Abstract
CYP2D6, a cytochrome P450 (CYP) enzyme, metabolizes codeine to morphine. Within the human body, 0-15% of codeine undergoes O-demethylation by CYP2D6 to form morphine, a far stronger analgesic than codeine. Genetic polymorphisms in wild-type CYP2D6 (CYP2D6-wt) are known to cause poor-to-extensive metabolism of codeine and other CYP2D6 substrates. We have established a platform technology that allows stable expression of human CYP genes from chromosomal loci of baker's yeast cells. Four CYP2D6 alleles, (i) chemically synthesized CYP2D6.1, (ii) chemically synthesized CYP2D6-wt, (iii) chemically synthesized CYP2D6.10, and (iv) a novel CYP2D6.10 variant CYP2D6-C (i.e., CYP2D6.10A122V) isolated from a liver cDNA library, were cloned for chromosomal integration in yeast cells. When expressed in yeast, CYP2D6.10 enzyme shows weak activity compared with CYP2D6-wt and CYP2D6.1 which have moderate activity, as reported earlier. Surprisingly, however, the CYP2D6-C enzyme is far more active than CYP2D6.10. More surprisingly, although CYP2D6.10 is a known low metabolizer of codeine, yeast cells expressing CYP2D6-C transform >70% of codeine to morphine, which is more than twice that of cells expressing the extensive metabolizers, CYP2D6.1, and CYP2D6-wt. The latter two enzymes predominantly catalyze formation of codeine's N-demethylation product, norcodeine, with >55% yield. Molecular modeling studies explain the specificity of CYP2D6-C for O-demethylation, validating observed experimental results. The yeast-based CYP2D6 expression systems, described here, could find generic use in CYP2D6-mediated drug metabolism and also in high-yield chemical reactions that allow the formation of regio-specific dealkylation products.
- Published
- 2018
9. Comparison of a triple-quadrupole and a quadrupole time-of-flight mass analyzer to quantify 16 opioids in human plasma
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Johan Viaene, Bieke Dejaegher, Debby Mangelings, Yvan Vander Heyden, Katrien Lanckmans, Analytical Chemistry and Pharmaceutical Technology, Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, Experimental Pharmacology, and Department of Analytical Chemistry, Applied Chemometrics and Molecular Modelling
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Clinical Biochemistry ,Analytical chemistry ,Pharmaceutical Science ,Sensitivity and Specificity ,030226 pharmacology & pharmacy ,01 natural sciences ,Mass Spectrometry ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Norcodeine ,Drug Discovery ,medicine ,Humans ,Solid phase extraction ,Norbuprenorphine ,Spectroscopy ,Chromatography ,Opioids ,UHPLC–MS ,Triple-quadrupole mass analyzer (QqQ) ,Quadrupole time-of-flight mass analyzer (QToF) ,Accuracy profile ,Matrix effects ,Chemistry ,010401 analytical chemistry ,Reproducibility of Results ,Repeatability ,Reference Standards ,Opioid-Related Disorders ,Hydromorphone ,Dihydrocodeine ,0104 chemical sciences ,Triple quadrupole mass spectrometer ,Analgesics, Opioid ,Substance Abuse Detection ,Calibration ,Tilidine ,Chromatography, Liquid ,medicine.drug - Abstract
The aim of this work is to study whether a quadrupole time-of-flight (QToF) mass analyzer, coupled to an ultra high performance liquid chromatography (UHPLC) system, can be a valuable alternative for a triple-quadrupole (QqQ) mass analyzer, for quantitative toxicological purposes. The case study considered was the quantification of 16 opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, morphine, norbuprenorphine, norcodeine, norfentanyl, oxycodone, oxymorphone, pholcodine and tilidine) in human plasma. Both methods were validated in parallel in terms of selectivity, matrix effects, extraction recovery, carry-over, bias, precision and sensitivity. Accuracy-profile methodology was used to determine the optimal calibration model, and to estimate bias, repeatability, intermediate precision and total error. Selectivity was demonstrated for all opioids and deuterated analogues, except for codeine-d3 on the UHPLC-QTOF. For most compounds, extraction recoveries were in the range 60 to 80% on both systems, except for the synthetic analogues, buprenorphine, fentanyl and tilidine, where large variability is observed. Carry-over was negligible on both systems. For different opioids, the optimal calibration model was different between the systems. The accuracy profiles of the majority of the opioids indicated that, over the entire tested concentration range, for more than 5% of the future measurements, total errors are expected to exceed the a priori defined 15% acceptance limit. For some exceptions, however, the measurements even suffer from total errors above 30%, which can be attributed to the solid phase extraction procedure that was applied as sample pretreatment technique. Sensitivity was generally tenfold better on the LC-QToF system, probably due to the difference in ion choice for quantification between both systems. In conclusion, the best performing system seemed to depend on the compound, on the parameter and even on the concentration. Accuracy profiles clearly provided valuable information complementary to that obtained in classical validation tests, and therefore preferably are taken into account when deciding on a method's performance.
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- 2016
10. Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths
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Joachim Frost, Lars Slørdal, Ivar Skjåk Nordrum, Trine N. Løkken, and Arne Helland
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Male ,Poison control ,01 natural sciences ,Mass Spectrometry ,chemistry.chemical_compound ,0302 clinical medicine ,Norcodeine ,Tissue Distribution ,Morphine ,Norway ,Solid Phase Extraction ,Middle Aged ,Adipose Tissue ,Cytochrome P-450 CYP2D6 ,Anesthesia ,Toxicity ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,CYP2D6 ,Genotype ,Substance-Related Disorders ,Pathology and Forensic Medicine ,Forensic Toxicology ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,030216 legal & forensic medicine ,Muscle, Skeletal ,Aged ,Brain Chemistry ,Morphine Derivatives ,Codeine ,business.industry ,010401 analytical chemistry ,Forensic toxicology ,0104 chemical sciences ,Vitreous Body ,Codeine-6-glucuronide ,Endocrinology ,chemistry ,Postmortem Changes ,business ,Law ,Chromatography, Liquid - Abstract
This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.
- Published
- 2016
11. Quantification of methadone, buprenorphine, naloxone, opioids, and their derivates in whole blood by liquid chromatography-high-resolution mass spectrometry: Analysis of their involvement in fatal forensic cases
- Author
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Zoubir Djerada, Claire Gozalo, Damien Vautier, Olivier Oget, Cyril Haudecoeur, Hélène Marty, Celine Konecki, Catherine Feliu, Yoann Cazaubon, Laurent Binet, Aurélie Fouley, Laboratoire de Pharmacologie et Toxicologie [CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), and Université de Reims Champagne-Ardenne (URCA)
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Liquid-Liquid Extraction ,Clinical Biochemistry ,Propoxyphene ,030226 pharmacology & pharmacy ,01 natural sciences ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Forensic Toxicology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Norcodeine ,Limit of Detection ,Naloxone ,medicine ,Humans ,Norbuprenorphine ,Chromatography, High Pressure Liquid ,ComputingMilieux_MISCELLANEOUS ,Chromatography ,Opiate Alkaloids ,010401 analytical chemistry ,Codeine ,Reproducibility of Results ,Cell Biology ,General Medicine ,Dihydrocodeine ,0104 chemical sciences ,3. Good health ,chemistry ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Linear Models ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Morphine ,Methadone ,medicine.drug ,Buprenorphine - Abstract
Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine…). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid–liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39–100 µg/L) and norbuprenorphine (0.20–100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.
- Published
- 2020
12. Codeine accumulation and elimination in larvae, pupae, and imago of the blowfly Lucilia sericata and effects on its development
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Claude Wyss, Patrice Mangin, Hicham Kharbouche, Frank Sporkert, Christian Giroud, Christophe Champod, Daniel Cherix, and Marc Augsburger
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Narcotics ,Veterinary medicine ,animal structures ,Swine ,Liver/chemistry ,Lucilia ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,Codeine/analogs & derivatives/analysis/toxicity ,Toxicology ,Forensic Toxicology ,Norcodeine ,Larva/chemistry ,parasitic diseases ,Pupa/chemistry ,medicine ,Animals ,Post-mortem interval ,Larva ,Diptera/chemistry ,Morphine ,biology ,Codeine ,Diptera ,ddc:614.1 ,fungi ,Pupa ,biology.organism_classification ,Codeine/analogs & derivatives ,Codeine/analysis ,Morphine/analysis ,Narcotics/analysis ,Narcotics/toxicity ,Entomotoxicology ,Liver ,Narcotics/analysis/toxicity ,medicine.drug - Abstract
The aim of this study was to evaluate the reliability of insect larvae as samples for toxicological investigations. For this purpose, larvae of Lucilia sericata were reared on samples of minced pig liver treated with different concentrations of codeine: therapeutic, toxic, and potentially lethal doses. Codeine was detected in all tested larvae, confirming the reliability of these specimens for qualitative toxicology analysis. Furthermore, concentrations measured in larvae were correlated with levels in liver tissue. These observations bring new elements regarding the potential use of opiates concentrations in larvae for estimation of drug levels in human tissues. Morphine and norcodeine, two codeine metabolites, have been also detected at different concentrations depending on the concentration of codeine in pig liver and depending on the substance itself. The effects of codeine on the development of L. sericata were also investigated. Results showed that a 29-h interval bias on the evaluation of the larval stage duration calculated from the larvae weight has to be considered if codeine was present in the larvae substrate. Similarly, a 21-h interval bias on the total duration of development, from egg to imago, has to be considered if codeine was present in the larvae substrate.
- Published
- 2018
13. Tracking narcotics consumption at a Southwestern U.S. university campus by wastewater-based epidemiology
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Rolf U. Halden, Adam J. Gushgari, Joshua C. Steele, and Erin M. Driver
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Narcotics ,Environmental Engineering ,Universities ,Health, Toxicology and Mutagenesis ,010501 environmental sciences ,Wastewater ,01 natural sciences ,Fentanyl ,Heroin ,chemistry.chemical_compound ,Norcodeine ,medicine ,Southwestern United States ,Environmental Chemistry ,Waste Management and Disposal ,0105 earth and related environmental sciences ,business.industry ,010401 analytical chemistry ,Codeine ,Pollution ,0104 chemical sciences ,chemistry ,Anesthesia ,Morphine ,Benzoylecgonine ,business ,Oxycodone ,Water Pollutants, Chemical ,medicine.drug ,Buprenorphine ,Environmental Monitoring - Abstract
Wastewater-based epidemiology (WBE) was applied to estimate the consumption of twelve narcotics within a Southwestern U.S. university campus. Seven consecutive 24-hour composite raw wastewater samples (n = 80) were obtained once per month from sampling locations capturing >95% of campus-generated wastewater. Samples were analyzed for indicators of consumption of morphine, codeine, oxycodone, heroin, fentanyl, methadone, buprenorphine, amphetamine, methylphenidate, alprazolam, cocaine, and MDMA using LC–MS/MS. Eleven indicator compounds (oxycodone, codeine, norcodeine, 6-acetylmorphine, EDDP, amphetamine, alprazolam, alpha-hydroxyalprazolam, cocaine, benzoylecgonine, and MDMA) occurred at 100% detection frequency across the study, followed by morphine-3-glucuronide (98%), noroxycodone (95%), methylphenidate (90%), heroin (7%), norfentanyl (7%), and fentanyl (5%). Estimates of average narcotics consumption ranked as follows in units of mg/day/1000 persons: heroin (474 ± 32), cocaine (551 ± 49), amphetamine (256 ± 12), methylphenidate (236 ± 28), methadone (72 ± 8), oxycodone (80 ± 6), alprazolam (60 ± 2), MDMA (88 ± 35), codeine (50 ± 4), and morphine (18 ± 3). This campus-based WBE study yielded baseline data on 12 narcotics for a U.S. campus and demonstrated for the first time the feasibility of detecting the fentanyl metabolite norfentanyl in this setting.
- Published
- 2018
14. Quantitative Analysis of 26 Opioids, Cocaine, and Their Metabolites in Human Blood by Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry
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Nathalie Kummer, Sarah M.R. Wille, Evi Ruyssinckx, Vincent Di Fazio, María del Mar Ramírez Fernández, and Nele Samyn
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Pharmacology ,Pholcodine ,Chromatography ,Substance-Related Disorders ,Chemistry ,Elution ,Hydromorphone ,Sensitivity and Specificity ,Analgesics, Opioid ,Substance Abuse Detection ,Norcodeine ,Cocaine ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,Oxymorphone ,medicine ,Morphine ,Humans ,Pharmacology (medical) ,Quantitative analysis (chemistry) ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
A sensitive and selective ultra performance liquid chromatographic-tandem mass spectrometric method was developed and fully validated for the simultaneous determination of (in order of chromatographic elution) methylecgonine, pholcodine, morphine, hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-Monoacetylmorphine (6-MAM), hydrocodone, ethylmorphine, norfentanyl, benzoylecgonine, tramadol, normeperidine, meperidine, cocaine, pentazocine, cocaethylene, fentanyl, norbuprenorphine, 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, propoxyphene, and methadone in blood. The matrixes analyzed during the validation experiments were as follows: citrated blank plasma for calibrators, fluoride blank plasma for internal quality control (QC), lyophilized serum for external QC, fluoride plasma and whole blood for authentic samples, and lyophilized serum and whole blood for proficiency testing schemes. Samples were extracted with cation exchange solid-phase extraction cartridges. The target drugs were separated and quantified in a chromatographic run of 8.1 minutes using 0.1% formic acid in water and methanol (with 0.1% formic acid) as mobile phase. The limit of quantification ranged from 0.5 to 2.5 ng/mL depending on the compound and the therapeutic concentration. The intra- and interassay precision was less than 15% for all the compounds (except for pentazocine and EDDP, which was20%) determined with 2 internal and 2 external QC samples, and the bias was within ±15% (except for methylecgonine, which was20%). Extraction efficiency was greater than 70% for all the compounds except for EDDP. Matrix effects were evaluated with authentic blood samples (n = 10), and they ranged from 47 to 95%, but they were compensated for most analytes using deuterated analogs as internal standards. Prepared samples were stable for 62 hours in the autosampler. This method was successfully applied to authentic samples (n = 120), involving the use of heroin, cocaine, tramadol, and methadone, and to proficiency testing schemes.
- Published
- 2013
15. Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects
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Jason M. White, Heather M. James, Eloise A. Gelston, Andrew A. Somogyi, Olga Vlagislavovna Lopatko, Helmut Schmidt, and Janet K. Coller
- Subjects
Pharmacology ,CYP2D6 ,business.industry ,Codeine ,Codeine Phosphate ,UGT2B7 ,Norcodeine ,medicine ,Morphine ,Pharmacology (medical) ,business ,medicine.drug ,Buprenorphine ,Methadone - Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Although not well recognized, methadone inhibits CYP2D6 in vivo and in vitro and UGT2B7 and 2B4 in vitro. • We aimed to investigate the effect of methadone on the pathways of codeine metabolism, namely O-demethylation (CYP2D6), 6-glucuronidation (UGT2B4/7) and N-demethylation (CYP3A4/2C8), in subjects maintained on methadone or buprenorphine as a control. WHAT THIS STUDY ADDS • Compared with subjects on buprenorphine, methadone reduced the clearance of codeine to morphine and to codeine-6-glucuronide but had no effect on norcodeine formation. • Plasma morphine concentrations remained unchanged, as although its formation was reduced, its metabolism to M3G and M6G was also reduced. • Metabolic drug interactions with methadone cannot assume substrate-dependent inhibition. AIMS To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS The urinary metabolic ratio for O-demethylation was significantly higher (P= 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P= 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P= 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.
- Published
- 2012
16. Rapid wide-scope screening of drugs of abuse, prescription drugs with potential for abuse and their metabolites in influent and effluent urban wastewater by ultrahigh pressure liquid chromatography–quadrupole-time-of-flight-mass spectrometry
- Author
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Ramon Díaz, Félix Hernández, María Ibáñez, Lubertus Bijlsma, and Juan V. Sancho
- Subjects
Ultrahigh pressure liquid chromatography ,Electrospray ,Prescription Drugs ,Time Factors ,Metabolite ,Wide-scope screening ,Mass spectrometry ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,chemistry.chemical_compound ,MSE ,Norcodeine ,Isomerism ,Fragmentation (mass spectrometry) ,medicine ,Environmental Chemistry ,Solid phase extraction ,Chromatography, High Pressure Liquid ,Spectroscopy ,Chemical ionization ,Chromatography ,Illicit Drugs ,Chemistry ,Time-of-flight mass spectrometry ,Urban wastewater ,Water ,Illicit drugs of abuse ,Water Pollutants, Chemical ,medicine.drug - Abstract
This work illustrates the potential of hybrid quadrupole-time-of-flight mass spectrometry (QTOF MS) coupled to ultrahigh pressure liquid chromatography (UHPLC) to investigate the presence of drugs of abuse in wastewater. After solid-phase extraction with Oasis MCX cartridges, seventy-six illicit drugs, prescription drugs with potential for abuse, and metabolites were investigated in the samples by TOF MS using electrospray interface under positive ionization mode, with MS data acquired over an m/z range of 50–1000 Da. For 11 compounds, reference standards were available, and experimental data (e.g., retention time and fragmentation data) could be obtained, facilitating a more confident identification. The use of a QTOF instrument enabled the simultaneous application of two acquisition functions with different collision energies: a low energy (LE) function, where none or poor fragmentation took place, and a high energy (HE) function, where fragmentation in the collision cell was promoted. This approach, known as MSE, enabled the simultaneous acquisition of full-spectrum accurate mass data of both protonated molecules and fragment ions in a single injection, providing relevant information that facilitates the rapid detection and reliable identification of these emerging contaminants in the sample matrices analyzed. In addition, isomeric compounds, like the opiates, morphine and norcodeine, could be discriminated by their specific fragments observed in HE TOF MS spectra, without the need of reference standards. UHPLC–QTOF MS was proven to be a powerful and efficient technique for rapid wide-scope screening and identification of many relevant drugs in complex matrices, such as influent and effluent urban wastewater. This work has been developed under financial support provided by the University Jaume I-Fundación Bancaixa (project reference: P1 1B2007-13) and the Spanish Ministry of Education and Science (projects reference: CTQ2009-12347 and CTM2006-07711)
- Published
- 2011
17. Urine testing for norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives
- Author
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Beverly Cawthon, Yale H. Caplan, Frank Moser, Rebecca Heltsley, Tim Robert, Anne Zichterman, Edward J. Cone, and David L. Black
- Subjects
Pain ,Pharmacology ,Medication Adherence ,Pathology and Forensic Medicine ,Forensic Toxicology ,Norcodeine ,Tandem Mass Spectrometry ,medicine ,Humans ,Hydrocodone ,False Negative Reactions ,Oxymorphone ,Codeine ,business.industry ,Forensic toxicology ,Norhydrocodone ,Hydromorphone ,Dihydrocodeine ,Analgesics, Opioid ,Morphinans ,business ,Law ,Oxycodone ,Chromatography, Liquid ,medicine.drug - Abstract
Urine drug testing of pain patients provides objective information to health specialists regarding patient compliance, diversion, and concurrent illicit drug use. Interpretation of urine test results for semi-synthetic opiates can be difficult because of complex biotransformations of parent drug to metabolites that are also available commercially and may be abused. Normetabolites such as norcodeine, norhydrocodone and noroxycodone are unique metabolites that are not available commercially. Consequently, detection of normetabolite in specimens not containing parent drug, provides conclusive evidence that the parent drug was consumed. The goal of this study was to evaluate the prevalence and patterns of the three normetabolites, norcodeine, norhydrocodone and noroxycodone, in urine specimens of pain patients treated with opiates. Urine specimens were hydrolyzed with beta-glucuronidase and analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay for the presence of codeine, norcodeine, morphine, hydrocodone, norhydrocodone, hydromorphone, dihydrocodeine, oxycodone, noroxycodone, and oxymorphone. The limit of quantitation (LOQ) for these analytes was 50ng/mL. The study was approved by an Institutional Review Board. Of the total specimens (N=2654) tested, 71.4% (N=1895) were positive (>or=LOQ) for one or more of the analytes. The prevalence (%) of positive results for codeine, hydrocodone and oxycodone was 1.2%, 26.1%, and 36.2%, respectively, and the prevalence of norcodeine, norhydrocodone and noroxycodone was 0.5%, 22.1%, and 31.3%, respectively. For specimens containing normetabolite, the prevalence of norcodeine, norhydrocodone and noroxycodone in the absence of parent drug was 8.6%, 7.8% and 9.4%, respectively. From one-third to two-thirds of these specimens also did not contain other metabolites that could have originated from the parent drug. Consequently, the authors conclude that inclusion of norcodeine, norhydrocodone and noroxycodone is useful in interpretation of opiate drug source and reduces potential false negatives that would occur without tests for these unique metabolites.
- Published
- 2010
18. Bioconversion of codeine to semi-synthetic opiate derivatives by the cyanobacterium Nostoc muscorum
- Author
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Somayeh Niknam, Mojtaba Tabatabaei Yazdi, Mohammad Ali Faramarzi, Hossein Rastegar, Khosrou Abdi, and Mohsen Amini
- Subjects
Cyanobacteria ,Chromatography ,biology ,Physiology ,Bioconversion ,Chemistry ,Alkaloid ,Codeine ,General Medicine ,biology.organism_classification ,Applied Microbiology and Biotechnology ,Norcodeine ,Biotransformation ,medicine ,Morphine ,Opiate ,Biotechnology ,medicine.drug - Abstract
Very limited studies have been done to investigate the algal biotransformation of codeine to its opioid derivatives. On the other hand, microalgae have been recently introduced as potential tools for green synthesis of various organic compounds. In the present work, the capability of biotransformation of codeine by a locally isolate strain of cyanobacterium, Nostoc muscorum, was evaluated. Incubation of the whole cells of Nostoc muscorum with codeine (I) under continuous light photoregime of 60 μmol photons/m2s at 25°C for 5 days gave rise to four transformation products. The bioproducts were separated by gas chromatography and identified as 6-acetylcodeine (II), oxycodone (III), norcodeine (IV), morphine (V) and based on their mass spectra. Observed modifications included O-demethylation, N-demethylation, C6-acetylation, C14-hydroxilation, Δ7-reduction, and C6-oxidation. The ability of N. muscorum to convert codeine to oxycodone (III) represents an uncommon pattern of codeine metabolism in microorganisms that may be of industrial importance.
- Published
- 2009
19. Trace determination of cannabinoids and opiates in wastewater and surface waters by ultra-performance liquid chromatography–tandem mass spectrometry
- Author
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Mª Rosa Boleda, Mª Teresa Galceran, and Francesc Ventura
- Subjects
Opium ,Mass spectrometry ,Tandem mass spectrometry ,Waste Disposal, Fluid ,Biochemistry ,Analytical Chemistry ,Norcodeine ,Tandem Mass Spectrometry ,Liquid chromatography–mass spectrometry ,medicine ,media_common.cataloged_instance ,Solid phase extraction ,European union ,media_common ,Chromatography ,Cannabinoids ,Chemistry ,Organic Chemistry ,Selected reaction monitoring ,Reproducibility of Results ,Water ,General Medicine ,Water Pollutants, Chemical ,Chromatography, Liquid ,Waste disposal ,medicine.drug - Abstract
A fast and reliable method using solid-phase extraction and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed for the simultaneous detection, identification and quantification of several central nervous system depressor drugs of abuse such as cannabinoids (Delta9-tetrahydrocannabinol, THC) and opiates (morphine, codeine, heroin, methadone, fentanyl) and their metabolites in water samples. Compounds were extracted from water by using Oasis HLB cartridges. After SPE enrichment, the selected depressor drugs, under UPLC optimized conditions, were separated in less than 8 min. Electrospray (ESI) tandem MS in positive ion mode and selected reaction monitoring was used for quantification. ESI-MS/MS conditions such as capillary and cone voltages, source and desolvation temperatures and cone and desolvation gas flow rates have been optimized and MS and MS/MS spectra of the studied compounds were obtained. At the working conditions four identification points were obtained as required by European Union guidelines for analysis by LC-MS/MS. Quality parameters (intra-day and inter-day precisions) for each analyte have been established in three different matrixes (purified, surface and waste waters). Recoveries were generally higher than 70% and instrumental quantification limits and limits of quantification were in the low pg and ng/l range, respectively. Finally, the method has been applied to the analysis of influent and effluents wastewaters and natural water samples from Catalonia (NE Spain) where the presence of several opiates such as morphine, codeine, norcodeine 2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine and methadone and cannnabinoids such as THC and 11-nor-carboxy-Delta9-tetrahydrocannabinol has been demonstrated.
- Published
- 2007
20. Determination of medicinal and illicit drugs in post mortem dental hard tissues and comparison with analytical results for body fluids and hair samples
- Author
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Markus Jörg Altenburger, Jürgen Kempf, Merja A. Neukamm, Volker Auwärter, and Miriam Klima
- Subjects
Drug ,Male ,Substance-Related Disorders ,media_common.quotation_subject ,Root canal ,Dentistry ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Norcodeine ,stomatognathic system ,medicine ,Humans ,030216 legal & forensic medicine ,Forensic Pathology ,media_common ,business.industry ,Illicit Drugs ,010401 analytical chemistry ,Codeine ,Forensic toxicology ,Middle Aged ,0104 chemical sciences ,Promethazine ,Substance Abuse Detection ,stomatognathic diseases ,medicine.anatomical_structure ,Postmortem Changes ,Nordazepam ,Pulp (tooth) ,Female ,business ,Law ,Tooth ,medicine.drug ,Hair - Abstract
In burnt or skeletonized bodies dental hard tissue sometimes is the only remaining specimen available. Therefore, it could be used as an alternative matrix in post mortem toxicology. Additionally, analysis of dental tissues could provide a unique retrospective window of detection. For forensic interpretation, routes and rates of incorporation of different drugs as well as physicochemical differences between tooth root, tooth crown and carious material have to be taken into account. In a pilot study, one post mortem tooth each from three drug users was analyzed for medicinal and illicit drugs. The pulp was removed in two cases; in one case the tooth was root canal treated. The teeth were separated into root, crown and carious material and drugs were extracted from the powdered material with methanol under ultrasonication. The extracts were screened for drugs by LC-MS n (ToxTyper™) and quantitatively analyzed with LC-ESI-MS/MS in MRM mode. The findings were compared to the analytical results for cardiac blood, femoral blood, urine, stomach content and hair. In dental hard tissues, 11 drugs (amphetamine, MDMA, morphine, codeine, norcodeine, methadone, EDDP, fentanyl, tramadol, diazepam, nordazepam, and promethazine) could be detected and concentrations ranged from approximately 0.13pg/mg to 2,400pg/mg. The concentrations declined in the following order: carious material>root>crown. Only the root canal treated tooth showed higher concentrations in the crown than in the root. In post mortem toxicology, dental hard tissue could be a useful alternative matrix facilitating a more differentiated consideration of drug consumption patterns, as the window of detection seems to overlap those for body fluids and hair.
- Published
- 2015
21. Too Much of a Good Thing
- Author
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Juraj Sprung, Erica D. Wittwer, and Wayne T. Nicholson
- Subjects
Norcodeine ,Chemistry ,Extensive metabolizer ,medicine ,Poor metabolizer ,Prodrug ,Combinatorial chemistry ,medicine.drug ,Narcotic Effects - Abstract
This case discusses the drug–gene interaction between cytochrome P450 2D6 and the prodrug codeine resulting in enhanced narcotic effects.
- Published
- 2015
22. Breaking the Codeine
- Author
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Randal O. Dull, Clint Christensen, and Nathan G. Orgain
- Subjects
Quinidine ,Codeine ,Prodrug ,Pharmacology ,digestive system ,Codeine-6-glucuronide ,chemistry.chemical_compound ,Norcodeine ,Hydrocodone ,chemistry ,medicine ,Morphine ,Tramadol ,skin and connective tissue diseases ,medicine.drug - Abstract
This case discusses the pharmacokinetic interaction between codeine and quinidine. Codeine is a prodrug, metabolized to the active compound morphine by CYP2D6, quinidine is a 2D6 inhibitor.
- Published
- 2015
23. Codeine Can’t Do It
- Author
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Erica D. Wittwer, Toby N. Weingarten, Katarina Bojanić, Juraj Sprung, and Wayne T. Nicholson
- Subjects
Codeine-6-glucuronide ,chemistry.chemical_compound ,Norcodeine ,chemistry ,Analgesic ,Codeine ,medicine ,Morphine ,Dextromethorphan ,Prodrug ,Pharmacology ,Active metabolite ,medicine.drug - Abstract
This case discusses a pharmacokinetic interaction between the prodrug codeine and fluoxetine. Codeine is converted to its active metabolite morphine by cytochrome P450 2D6. Fluoxetine is a 2D6 inhibitor.
- Published
- 2015
24. Solid-state IR-LD spectroscopy of codeine and N-norcodeine derivatives
- Author
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Tsonko Kolev, Rumyana Bakalska, and Bojidarka B. Ivanova
- Subjects
Chemistry ,Codeine ,Solid-state ,Analytical chemistry ,Infrared spectroscopy ,General Chemistry ,ir-ld spectroscopy ,3-ethoxy-4-(n-norcodeino-)-cyclobutene-1,2-dione ,Photochemistry ,codeine dihydrogenphosphate ,Norcodeine ,Liquid crystal ,Organic systems ,Materials Chemistry ,medicine ,Spectroscopy ,QD1-999 ,medicine.drug - Abstract
Linear-dichroic infrared spectra (IR-LD) of 3-ethoxy-4-(N-norcodeino-)cyclobutene-1,2-dione (1) and codeine dihydrogenphosphate (Codeinum phosphoricum) (2), oriented as solid suspensions in nematic liquid crystals, have been measured. IR characteristic band assignments were made, and used in stereo-structural predictions. The results were compared with crystallographic structures of similar organic systems, and found to be in good agreement.
- Published
- 2006
25. Validation of an automated solid-phase extraction method for the analysis of 23 opioids, cocaine, and metabolites in urine with ultra-performance liquid chromatography-tandem mass spectrometry
- Author
-
María del Mar Ramírez Fernández, Nele Samyn, Natalie Kummer, Sarah M.R. Wille, Filip Van Durme, and Vincent Di Fazio
- Subjects
Health, Toxicology and Mutagenesis ,Toxicology ,Analytical Chemistry ,chemistry.chemical_compound ,Automation ,Cocaethylene ,Norcodeine ,Cocaine ,Liquid chromatography–mass spectrometry ,Limit of Detection ,Tandem Mass Spectrometry ,medicine ,Environmental Chemistry ,Humans ,Sample preparation ,Solid phase extraction ,Norbuprenorphine ,Chromatography, High Pressure Liquid ,Chemical Health and Safety ,Chromatography ,Solid Phase Extraction ,Dihydrocodeine ,Analgesics, Opioid ,chemistry ,Benzoylecgonine ,medicine.drug - Abstract
The aim of this work was to automate a sample preparation procedure extracting morphine, hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-monoacetyl-morphine, hydrocodone, ethylmorphine, benzoylecgonine, cocaine, cocaethylene, tramadol, meperidine, pentazocine, fentanyl, norfentanyl, buprenorphine, norbuprenorphine, propoxyphene, methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine from urine samples. Samples were extracted by solid-phase extraction (SPE) with cation exchange cartridges using a TECAN Freedom Evo 100 base robotic system, including a hydrolysis step previous extraction when required. Block modules were carefully selected in order to use the same consumable material as in manual procedures to reduce cost and/or manual sample transfers. Moreover, the present configuration included pressure monitoring pipetting increasing pipetting accuracy and detecting sampling errors. The compounds were then separated in a chromatographic run of 9 min using a BEH Phenyl analytical column on a ultra-performance liquid chromatography – tandem mass spectrometry system. Optimization of the SPE was performed with different wash conditions and elution solvents. Intra- and inter-day relative standard deviations (RSDs) were within +15% and bias was within + +15% for most of the compounds. Recovery was >69% (RSD < 11%) and matrix effects ranged from 1 to 26% when compensated with the internal standard. The limits of quantification ranged from 3 to 25 ng/mL depending on the compound. No crosscontamination in the automated SPE system was observed. The extracted samples were stable for 72 h in the autosampler (488C). This method was applied to authentic samples (from forensic and toxicology cases) and to proficiency testing schemes containing cocaine, heroin, buprenorphine and methadone, offering fast and reliable results. Automation resulted in improved precision and accuracy, and a minimum operator intervention, leading to safer sample handling and less time-consuming procedures.
- Published
- 2014
26. Evaluation of Opiate Separation by High-Resolution Electrospray Ionization-Ion Mobility Spectrometry/Mass Spectrometry
- Author
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Laura M. Matz and Herbert H. Hill
- Subjects
Narcotics ,Normorphine ,Morphine Derivatives ,Spectrometry, Mass, Electrospray Ionization ,Electrospray ,Chromatography ,Morphine ,Chemistry ,Electrospray ionization ,Mass spectrometry ,Analytical Chemistry ,Adduct ,Norcodeine ,Ion-mobility spectrometry–mass spectrometry ,medicine ,Molecule ,Indicators and Reagents ,medicine.drug - Abstract
The separation of opiates and the primary metabolites was evaluated with ESI-IMS/MS. Seven opiate molecules were analyzed, and spectra were shown for each compound. The IMS separation of two isomers (morphine and norcodeine) was shown with baseline separation. Differences in the mobilities were found for the nonacetylated, monoacetylated, and biacetylated compounds. In this study, two primary findings are reported. First, IMS can easily separate metabolic isomers, and second, the two-dimensional separation capability of IMS/MS can be employed to confidently identify and separate both the opiates and metabolites. Although previous IMS studies have shown the separation of isomers, this is the first example to show the capability of IMS to separate metabolic isomers (within 70 s), a significant advantage in high-throughput screening for pharmacokinetic studies. Second, the monoacetylated and biacetylated compounds were found to form more compact ions for the sodium adducts in comparison to the protonated molecular ions. On the basis of the mobilities, information on structures and conformation can be deduced when sodium and protonated ions are compared.
- Published
- 2001
27. Determination of Codeine in Human Plasma and Drug Formulation Using a Chemically Modified Electrode
- Author
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Ming-Ren Chang, Hsieh-Hsun Chung, Ying Shih, and Jyh-Myng Zen
- Subjects
Flow injection analysis ,Detection limit ,Calibration curve ,Analytical chemistry ,Analytical Chemistry ,chemistry.chemical_compound ,Norcodeine ,chemistry ,Nafion ,Standard addition ,Electrochemistry ,medicine ,Voltammetry ,medicine.drug ,Chemically modified electrode - Abstract
Both flow injection methodology and square-wave voltammetry were developed and evaluated for determining codeine in human plasma and pharmaceutical formulations using a Nafion/ruthenium oxide pyrochlore chemically modified electrode. Combining the electrocatalytic function of the ruthenium-oxide pyrochlore with charge-exclusion and the preconcentration features of Nafion perform well in codeine detection. Compared to a bare glassy carbon electrode, the chemically modified electrode exhibits a shift of the oxidation potential in cathodic direction and a marked enhancement of the current response. A linear calibration plot is obtained over the 0–32 μM range in 0.05 M HClO4 solution with a detection limit (3σ) of 10 nM in the square-wave voltammetric method. While, in flow-injection analysis, a linear calibration plot is obtained over the 0.5–40 μM range with a detection limit of 0.86 ng. Quantitative analysis was performed by the standard addition method for codeine content in human plasma and a commercially available drug.
- Published
- 1998
28. Simultaneous determination of codeine and it seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection
- Author
-
Sheila Shay, Huaibing He, Margaret Wood, Alastair J. J. Wood, and Yoseph Caraco
- Subjects
Normorphine ,Detection limit ,Chromatography ,Codeine ,Chemistry ,Reproducibility of Results ,General Chemistry ,Urine ,Sensitivity and Specificity ,High-performance liquid chromatography ,chemistry.chemical_compound ,Norcodeine ,Electrochemistry ,medicine ,Humans ,Spectrophotometry, Ultraviolet ,Solid phase extraction ,Sodium dodecyl sulfate ,Glucuronide ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
A sensitive and selective high-performance liquid chromatography method has been developed for the measurement of codeine and its seven metabolites, norcodeine, morphine, normorphine, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide and norcodeine glucuronide, in plasma and urine. The compounds were recovered from plasma and urine using solid-phase extraction with C18 cartridges and separated on a reversed-phase C8 column with a mobile phase consisting of 77% buffer (5 mM sodium phosphate monobasic and 0.70 mM sodium dodecyl sulfate, pH 2.35) and 23% acetonitrile. Codeine, norcodeine, codeine-6-glucuronide, norcodeine glucuronide and morphine-3-glucuronide were detected by ultraviolet detection at 214 nm, with a detection limit of 0.02 nmol/ml for each compound in plasma. Morphine-6-glucuronide, normorphine and morphine were monitored by electrochemical detection at 350 mV, with a detection limit of 0.003 nmol/ml for each compound in plasma. The assay showed good reproducibility and accuracy using external standardization. The recovery and inter-day variation for all compounds in plasma samples were 63.40-77.90% and 3.49-16.77% (R.S.D.) and while in urine were 64.98-90.13% and 2.93-9.96% (R.S.D.), respectively.
- Published
- 1998
29. Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes
- Author
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J. Säwe and Q. Y. Yue
- Subjects
Analgesic ,Drug Evaluation, Preclinical ,Propoxyphene ,In Vitro Techniques ,Pharmacology ,Mixed Function Oxygenases ,Norcodeine ,Cytochrome P-450 CYP2D6 Inhibitors ,Cytochrome P-450 CYP3A ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Pharmacology (medical) ,Enzyme Inhibitors ,CYP3A4 ,Codeine ,Chemistry ,General Medicine ,Biochemistry ,Microsomes, Liver ,Morphine ,Microsome ,medicine.drug - Abstract
Objective: The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 respectively. The formation rates of morphine by O-demethylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes. Results: Relatively high K m values were found for both O- and N-demethylations, suggesting a low affinity to the corresponding enzymes. The inhibitory effects of various drugs were found to be different for O- and N-demethylations. The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol inhibited the O-demethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong inhibitors of the N-demethylation of codeine. Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A. Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent. Conclusion: It seems that there was a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen for drugs which interact with these two important drug-metabolising enzymes.
- Published
- 1997
30. Effects of Ethanol on Ethylmorphine Metabolism in Isolated Rat Hepatocytes: Characterization by Means of a Multicompartmental Model
- Author
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Asbjørg S. Christophersen, Bjern Lillekjendlie, Bang Qian Xu, Anders Bjørneboe, Jørg Mørland, and Tor A. Aasmundstad
- Subjects
Male ,Health, Toxicology and Mutagenesis ,Glucuronidation ,Glucuronates ,In Vitro Techniques ,Toxicology ,Models, Biological ,chemistry.chemical_compound ,Norcodeine ,medicine ,Animals ,Ethylmorphine ,Rats, Wistar ,Pharmacology ,Normorphine ,Chromatography ,Ethanol ,Morphine ,Codeine ,Chemistry ,Metabolism ,Rats ,Liver ,Biochemistry ,medicine.drug - Abstract
Hepatic cytochrome P-450 enzymes mediate at least two important biotransformation pathways of codeine and ethylmorphine starting with either N-demethylation or O-dealkylation, producing polar metabolites which are then subsequently glucuronidated. The present study was designed to characterise the acute effects of ethanol on the metabolism of ethylmorphine and to compare it with the effects on codeine in suspensions of freshly isolated rat hepatocytes. Isolated rat hepatocytes from male Wistar rats were prepared by a collagenase perfusion method. Ethylmorphine, codeine and their metabolites were quantified by HPLC with UV detection. The total ethylmorphine elimination rate was reduced by 12% at 5mM and 38% at 100 mM ethanol. The corresponding percentages for codeine were 16 and 43%. In the presence of ethanol the concentrations of several intermediate and end products of ethylmorphine and codeine changed markedly from the control situation. The experimental data were applied to a mathematical compartmental linear model to estimate the influence of ethanol on the separate reaction rates in the two main metabolic pathways. The ratios between reaction rate constants in the ethylmorphine experiments at 100 and 0 mM ethanol were 0.65 for ethylmorphine-->norethylmorphine, 0.63 for norethylmorphine-->normorphine, 0.56 for ethylmorphine-->morphine, 0.49 for morphine-->normorphine, 0.31 for normorphine-->normorphine-3-glucuronide and 0.49 for morphine-->morphine-3-glucuronide. Almost similar effects of ethanol on codeine metabolism were found. In additional experiments, norethylmorphine or norcodeine (50 microM) was incubated with 5 mM to 100 mM of ethanol and the metabolism of both norethylmorphine and norcodeine was found to be inhibited by ethanol in a concentration-dependent manner. The glucuronidation of morphine and normorphine added in separate experiments was also inhibited by ethanol, from 22 to 36% for morphine-3-glucuronide and 30 to 60% for normorphine-3-glucuronide, respectively, in the presence of 5 mM to 100 mM of ethanol. It was concluded that all steps in the metabolism of ethylmorphine (and codeine) leading to the end products morphine-3-glucuronide and normorphine-3-glucuronide were inhibited by ethanol, and that the glucuronidation process were the ones most affected by ethanol.
- Published
- 1997
31. Separation of free and glucuronidated opioids by capillary electrophoresis in aqueous, binary and micellar media
- Author
-
Chao-Xuan Zhang and Wolfgang Thormann
- Subjects
Normorphine ,Chromatography ,Aqueous solution ,Organic Chemistry ,General Medicine ,Biochemistry ,Micellar electrokinetic chromatography ,Analytical Chemistry ,chemistry.chemical_compound ,Electrophoresis ,Norcodeine ,Capillary electrophoresis ,chemistry ,medicine ,Sodium dodecyl sulfate ,Ethylene glycol ,medicine.drug - Abstract
The separation behavior of free and glucuronidated opioids, including codeine, dihydrocodeine, morphine, norcodeine, normorphine, codeine-6-glucuronide, morphine-3-glucuronide, dihydromorphine, nordihydrocodeine, nordihydromorphine and dihydrocodeine-6-glucuronide, by capillary zone electrophoresis (CZE) and electrokinetic chromatography (EKC) in aqueous and binary media with ethylene glycol is reported. The opioids' charges and thus their separations are shown to be strongly dependent on buffer pH, particularly in the pH range 6–12. Unconjugated codeinoids are shown to be able to form cations whereas unconjugated morphinoids and the glucuronides are of amphoteric nature with pI values in the 9–10 range and around 5, respectively. Due to the similarity of most pKa values and chemical structures, all 12 opioids cannot be fully separated by aqueous and binary CZE. However, they can be resolved completley by aqueous EKC using 80 mM sodium dodecyl sulfate at pH 10.6. In EKC at pH 2.2 the cationic opioids strongly interact with the negatively charged dodecyl sulfate, migrate poorly resolved toward the positive electrode, are detected in the order of decreasing capacity factors and their elution times decrease with increasing surfactant concentration. With addition of ethylene glycol (up to 60%, v/v), the interaction between solutes and dodecyl sulfate is weakened and resolution is attained. An approach to measuring the viscosity of running buffers using a capillary electrophoresis apparatus is discussed.
- Published
- 1997
32. Octanol−, Chloroform−, and Propylene Glycol Dipelargonat−Water Partitioning of Morphine-6-glucuronide and Other Related Opiates
- Author
-
Alex Avdeef, Paul N. Shaw, Roger Knaggs, S.S. Davis, and David A. Barrett
- Subjects
Narcotics ,Octanol ,Octanols ,Chemical Phenomena ,chemistry.chemical_compound ,Norcodeine ,Drug Discovery ,medicine ,Normorphine ,Morphine Derivatives ,Chloroform ,Chromatography ,Chemistry, Physical ,Biological Transport ,Hydrogen-Ion Concentration ,Morphine-6-glucuronide ,Solutions ,Solvent ,Partition coefficient ,chemistry ,Lipophilicity ,Potentiometry ,Solvents ,Molecular Medicine ,medicine.drug - Abstract
The pKa and log P values of morphine-6-β-d-glucuronide (M6G) and morphine-3-β-d-glucuronide (M3G) and a range of structurally-related opiates (morphine, normorphine, codeine, norcodeine, 6-acetylmorphine, diacetylmorphine, and buprenorphine) were accurately measured using a potentiometric approach. The measured lipophilicity profiles (pH 2−11, 0.15 M KCl matrix) of M3G and M6G were compared using a proton donor solvent (chloroform) and a proton acceptor solvent (propylene glycol dipelargonate, PGDP), in addition to octanol. The log P values and lipophilicity profiles of M6G and M3G determined in octanol−water have confirmed the unexpectedly high lipophilicity of the two glucuronides. These results show the importance of measuring the effect of pH on lipophilicity, since log D (pH 7.4) values gave a notably different order of lipophilicity for the opiates compared with log P. M6G, but not M3G, showed significant differences in log P between different types of partitioning solvents. The observed order of li...
- Published
- 1996
33. The pharmacogenetics of codeine hypoalgesia
- Author
-
Søren H. Sindrup and Kim Brøsen
- Subjects
Pain Threshold ,Quinidine ,CYP2D6 ,Sparteine ,Pain ,Pharmacology ,digestive system ,Mixed Function Oxygenases ,Norcodeine ,Cytochrome P-450 Enzyme System ,Genetics ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Drug Interactions ,Enzyme Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,skin and connective tissue diseases ,chemistry.chemical_classification ,Polymorphism, Genetic ,Hypoalgesia ,Morphine ,Codeine ,Chemistry ,Analgesics, Opioid ,Debrisoquin ,Phenotype ,Cytochrome P-450 CYP2D6 ,Pharmacogenetics ,Oxidation-Reduction ,medicine.drug ,Tricyclic - Abstract
Codeine is an old drug that is still widely used to treat mild and moderate pain. It is mainly metabolised by glucuronidation, but minor pathways are N-demethylation to norcodeine and O-demethylation to morphine. The latter pathway depends on the genetically polymorphic CYP2D6 which is absent in 7% of the white population (PM) and present in the remainder (EM). Lack of influence of codeine on experimental pain in PM as well as in EM treated with the CYP2D6 blocker quinidine, who are both practically unable to convert codeine to morphine, has supported an old hypothesis that codeine acts through metabolically formed morphine. Possibly, local codeine O-demethylation in the CNS is of major importance for its hypoalgesic effect. Such a local morphine formation from codeine, which supposedly is also catalysed by CYP2D6, could explain why the hypoalgesic effect of codeine stems from morphine despite relatively low plasma levels of morphine after standard hypoalgesic doses of codeine. Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors and some neuroleptics. Less potent inhibitors, such as tricyclic antidepressants, will probably also reduce the pain relieving effect of codeine, since codeine has a low affinity for CYP2D6. Biosynthesis of morphine in humans may also include steps catalyse by CYP2D6. Experimental studies in large groups of EM and PM indicate that this may lead to interphenotype differences in pain tolerance.
- Published
- 1995
34. In vitrometabolism of specific CYP2D and CYP3A opioid substrates using rat liver S9 fractions and mass spectrometry reveal a severe metabolic impairment with increasing age
- Author
-
Pascal Vachon, Marie-Chantal Giroux, Sabrin Fuad Salmin, and Francis Beaudry
- Subjects
Pharmacology ,Chromatography ,Chemistry ,Clinical Biochemistry ,Codeine ,General Medicine ,030226 pharmacology & pharmacy ,Biochemistry ,3. Good health ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Norcodeine ,Opioid ,Oxymorphone ,Drug Discovery ,Toxicity ,medicine ,Morphine ,030212 general & internal medicine ,Molecular Biology ,Oxycodone ,Drug metabolism ,medicine.drug - Abstract
Codeine and oxycodone are opioids used to alleviate pain. The outcome of the treatment is ultimately related to their metabolism by Cytochromes P450 (CYPs). Depending on the drugs used, alterations in the metabolism of drugs by CYPs can lead to severe consequences including alterations in their efficacy, safety and toxicity. The objectives of this study were to develop a novel HPLC-MS/MS method capable of quantifying codeine and oxycodone along with specific metabolites using an isotopic dilution strategy and study the rate of formation of morphine (CYP2D), norcodeine (CYP3A), oxymorphone (CYP2D) and noroxycodone (CYP3A). The chromatographic separation was achieved using a Biobasic C18 100 x 1 mm column combined with an isocratic mobile phase composed of methanol and 10 mM ammonium acetate (40:60) at a flow rate of 75 μL/min. The mass spectrometer was operating in scan mode MS/MS and the analytical range was set at 10–10 000 nM. The precision (%RSD) and accuracy (%RE) observed were 4.4–11.5 and -9.1–6.1% respectively. Liver S9 fractions from 3-, 6-, 12-, and 18-month-old male Sprague Dawley rats were prepared and Michaelis Menten parameters were determined. The derived maximum enzyme velocity (Vmax) suggested a rapid saturation of the CYP2D and CYP3A active sites in the liver S9 fractions of 18 month-old rats. Moreover, metabolic stability of codeine and oxycodone in rat liver S9 fractions were significantly greater for the 18-month-old rats. This study suggests that there is an impairment of CYP2D and CYP3A metabolism in aging rats.
- Published
- 2016
35. Ethylmorphine o-deethylation in isolated rat hepatocytes
- Author
-
Tor A. Aasmundstad, Bang Qian Xu, Jørg Mørland, Anders Bjørneboe, and Asbjørg S. Christophersen
- Subjects
Pharmacology ,Quinidine ,Normorphine ,biology ,Chemistry ,Sparteine ,Cytochrome P450 ,Ethylmorphine ,Biochemistry ,medicine.anatomical_structure ,Norcodeine ,Hepatocyte ,medicine ,biology.protein ,medicine.drug ,Demethylation - Abstract
The O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M) co-segregates with debrisoquine/sparteine genetic polymorphism in man. CD O-demethylation is catalysed by cytochrome P450 2D1 (CYP2D1) in rats. In the present study, the O-deethylation of EM was examined and compared with that of CD in suspensions of freshly-isolated hepatocytes prepared by a collagenase method from Wistar rats with and without CYP2D1 inhibitors. Isolated hepatocytes were also prepared from Dark Agouti (DA) rats deficient in CYP2D1, and were incubated with EM or CD. EM, CD and their metabolites were quantified by HPLC with UV detection. EM had a similar pattern of metabolism to that of CD in suspensions of hepatocytes from Wistar rats. Both EM and CD were O-dealkylated to form M plus morphine-3-glucuronide (M3G) and N-demethylated to form norethylmorphine (NEM) or norcodeine (NCD), respectively, which were further metabolized to normorphine (NM) and finally glucuronidated to normorphine-3-glucuronide (NM3G). As compared to hepatocytes from Wistar rats, DA rats were characterized by a markedly decreased formation (70 approximately 75% reduction) of M plus M3G from both EM and CD. Quinine, quinidine, propafenone and sparteine all inhibited EM O-deethylation as well as CD O-demethylation. Quinine was the most potent inhibitor of both these O-dealkylations (Ki = 0.2 microM for both EM and CD, respectively). Quinine as well as the other inhibitors inhibited both EM and CD O-dealkylation competitively and with small differences in Ki versus EM and CD, respectively. The metabolism of EM to M plus M3G and that of CD to M plus M3G was highly correlated when results from the various separate cell suspensions were plotted. In conclusion all findings indicated that the enzyme responsible for O-demethylation of CD, CYP2D1 was also responsible for the O-deethylation of EM to M.
- Published
- 1995
36. Simultaneous assay of cocaine, heroin and metabolites in hair, plasma, saliva and urine by gas chromatography—mass spectrometry
- Author
-
Wen Ling Wang, William D. Darwin, and Edward J. Cone
- Subjects
Normorphine ,Trimethylsilyl Compounds ,Chromatography ,General Chemistry ,BSTFA ,Gas Chromatography-Mass Spectrometry ,Heroin ,Drug detection ,chemistry.chemical_compound ,Cocaethylene ,Norcodeine ,Cocaine ,chemistry ,Benzoylecgonine ,medicine ,Humans ,Indicators and Reagents ,Gas chromatography–mass spectrometry ,Saliva ,Ecgonine ,Hair ,medicine.drug - Abstract
As part of an ongoing research program on the development of drug detection methodology, we developed an assay for the simultaneous measurement of cocaine, heroin and metabolites in plasma, saliva, urine and hair by solid-phase extraction (SPE) and gas chromatography-mass spectrometry (GC-MS). The analytes that could be measured by this assay were the following: anhydroecgonine methyl ester; ecgonine methyl ester;. ecgonine ethyl ester; cocaine; cocaethylene; benzoylecgonine; cocaethylene; norcocaethylene; benzoylnorecgonine; codeine; morphine; norcodeine; 6-acetylmorphine; normorphine; and heroin. Liquid specimens were diluted, filtered and then extracted by SPE. Additional handling steps were necessary for the analysis of hair samples. An initial wash procedure was utilized to remove surface contaminants. Washed hair samples were extracted with methanol overnight at 40 degrees C. Both wash and extract fractions were collected, evaporated and purified by SPE. All extracts were evaporated, derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) and analyzed by GC-MS. The limit of detection (LOD) for cocaine, heroin and metabolites in biological specimens was approximately 1 ng/ml with the exception of norcodeine, normorphine and benzoylnorecgonine (LOD = 5 ng/ml). The LOD for cocaine, heroin and metabolites in hair was approximately 0.1 ng/mg of hair with the exception of norcodeine (LOD = 0.3 ng/mg) and normorphine and benzoylnorecgonine (LOD = 0.5 ng/mg). Coefficients of variation ranged from 3 to 26.5% in the hair assay. This assay has been successfully utilized in research on the disposition of cocaine, heroin and metabolites in hair, plasma, saliva and urine and in treatment studies.
- Published
- 1994
37. Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man
- Author
-
Q. Y. Yue, Torbjörn Tomson, and Juliette Säwe
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Metabolite ,Glucuronidation ,Glucuronates ,Excretion ,chemistry.chemical_compound ,Norcodeine ,Internal medicine ,Tobacco ,Genetics ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Active metabolite ,Normorphine ,Codeine ,business.industry ,Smoking ,Drug Synergism ,Carbamazepine ,Middle Aged ,Plants, Toxic ,Endocrinology ,chemistry ,Female ,business ,medicine.drug - Abstract
The inducibility of codeine metabolism by carbamazepine (CBZ) and cigarette smoking has been investigated. A single oral dose of 25 mg of codeine was given to seven epileptic patients before and after 3 weeks' regular CBZ treatment (400-600 mg per day). Codeine was also given to nine volunteers who were heavy smokers (20 cigarettes per day) and to nine non-smokers as controls. All subjects were found to be extensive metabolizers of codeine by O-demethylation. Urine was collected over 8 h following codeine intake. Codeine and the metabolites were analysed with HPLC. CBZ significantly increased the urinary excretion of the N-demethylated metabolite, norcodeine (NC) which led to a significant decrease in the metabolic ratio (MR) for N-demethylation. The O-demethylation was not significantly altered. The excretion of normorphine, an active metabolite formed through both O- and N-demethylation of codeine increased by almost three-fold after CBZ treatment. Contrary to CBZ treatment, cigarette smoking slightly but significantly induced the glucuronidation of codeine as shown by a decreased MR for glucuronidation in the smokers, while the O- and N-demethylations were not significantly changed as indicated by the similar MRs in smokers and in non-smokers. These results suggest that CBZ and cigarette smoking selectively induce different metabolizing enzymes. The polymorphic O-demethylation is relatively stable to these factors.
- Published
- 1994
38. Determination of codeine and its metabolites in microsomal incubates by high-performance liquid chromatography
- Author
-
P. Nicholas Shaw, David A. Barrett, and M. Pawula
- Subjects
Detection limit ,Chromatography ,Morphine ,Codeine ,Chemistry ,Metabolite ,General Chemistry ,High-performance liquid chromatography ,Rats ,Matrix (chemical analysis) ,chemistry.chemical_compound ,Norcodeine ,Electrochemistry ,Microsomes, Liver ,medicine ,Animals ,Spectrophotometry, Ultraviolet ,Quantitative analysis (chemistry) ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
A rapid and sensitive HPLC method has been developed for the determination of codeine, norcodeine and morphine in small volumes of a biological matrix, using a cyanopropyl column and a combination of coulometric and UV detection. The compounds were isolated using C18 solid-phase extraction cartridges prior to quantitative analysis. The limit of detection was 250 pg/ml for morphine and 5 ng/ml for both norcodeine and codeine. Recovery of each compound was greater than 90% and intra- and inter-assay precision was better than 10%. The method has been used to study the metabolism of codeine in microsomal incubations.
- Published
- 1994
39. Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths
- Author
-
Joachim Frost, Lars Slørdal, Arne Helland, and Ivar S. Nordrum
- Subjects
Adult ,Male ,Narcotics ,CYP2D6 ,Genotype ,Analgesic ,Pharmacology ,Polymerase Chain Reaction ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,Forensic Toxicology ,Norcodeine ,Cytochrome P-450 Enzyme System ,Medicine ,Humans ,Aged ,Morphine Derivatives ,Morphine ,business.industry ,Codeine ,Forensic toxicology ,Middle Aged ,Isoenzymes ,Opioid ,Toxicity ,Female ,business ,Law ,medicine.drug - Abstract
Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3 mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios.
- Published
- 2011
40. Automated solid-phase extraction-liquid chromatography-tandem mass spectrometry analysis of 6-acetylmorphine in human urine specimens: application for a high-throughput urine analysis laboratory
- Author
-
P. V. Robandt, H. M. Bui, Kevin L. Klette, and J. M. Scancella
- Subjects
Health, Toxicology and Mutagenesis ,Urinalysis ,Toxicology ,High-performance liquid chromatography ,Analytical Chemistry ,Specimen Handling ,chemistry.chemical_compound ,Forensic Toxicology ,Norcodeine ,Liquid chromatography–mass spectrometry ,medicine ,Environmental Chemistry ,Humans ,Solid phase extraction ,Derivatization ,Morphine Derivatives ,Chemical Health and Safety ,Chromatography ,Solid Phase Extraction ,Reversed-phase chromatography ,High-Throughput Screening Assays ,Substance Abuse Detection ,chemistry ,Gas chromatography ,Gas chromatography–mass spectrometry ,medicine.drug - Abstract
An automated solid-phase extraction-liquid chromatography- tandem mass spectrometry (SPE-LC-MS-MS) method using the Spark Holland Symbiosis Pharma SPE-LC coupled to a Waters Quattro Micro MS-MS was developed for the analysis of 6-acetylmorphine (6-AM) in human urine specimens. The method was linear (R² = 0.9983) to 100 ng/mL, with no carryover at 200 ng/mL. Limits of quantification and detection were found to be 2 ng/mL. Interrun precision calculated as percent coefficient of variation (%CV) and evaluated by analyzing five specimens at 10 ng/mL over nine batches (n = 45) was 3.6%. Intrarun precision evaluated from 0 to 100 ng/mL ranged from 1.0 to 4.4%CV. Other opioids (codeine, morphine, oxycodone, oxymorphone, hydromorphone, hydrocodone, and norcodeine) did not interfere in the detection, quantification, or chromatography of 6-AM or the deuterated internal standard. The quantified values for 41 authentic human urine specimens previously found to contain 6-AM by a validated gas chromatography (GC)-MS method were compared to those obtained by the SPE-LC-MS-MS method. The SPE-LC-MS-MS procedure eliminates the human factors of specimen handling, extraction, and derivatization, thereby reducing labor costs and rework resulting from human error or technique issues. The time required for extraction and analysis was reduced by approximately 50% when compared to a validated 6-AM procedure using manual SPE and GC-MS analysis.
- Published
- 2011
41. Improved Gas Chromatography–Mass Spectrometry Method for Simultaneous Identification and Quantification of Opiates in Urine as Propionyl and Oxime Derivatives
- Author
-
Mike Tanous, Cecelia A. Queen, Lance C. Presley, and Larry A. Broussard
- Subjects
Chromatography ,Chemistry ,Biochemistry (medical) ,Clinical Biochemistry ,Codeine ,Hydromorphone ,Norcodeine ,Hydrocodone ,Oxymorphone ,medicine ,Morphine ,Gas chromatography ,Gas chromatography–mass spectrometry ,medicine.drug - Abstract
Several authors have reviewed existing methods (1)(2)(3)(4)(5)(6)(7)(8)(9) or presented new techniques (6)(7)(8)(9)(10)(11) for the analysis and separation of codeine, morphine, and the keto-opiates hydrocodone, hydromorphone, oxycodone, and oxymorphone. We present a modification of previously published procedures (6)(10) that incorporates the use of methoxyamine after enzymatic hydrolysis to form methoxime derivatives of the keto-opiates, which are then extracted using solid-phase columns and derivatized with propionic anhydride/pyridine. We used a gas chromatography–mass spectrometry system composed of a model 5890 gas chromatograph with splitless injection, a model 5970 mass-selective detector (both from Hewlett Packard), and a DB-5 capillary column [15 m × 0.25 mm (i.d.); 0.25 μm film thickness; JW helium (flow rate, 0.7 mL/min; linear velocity, 38 cm/s) was used as the carrier gas. The temperature program was as follows: initial temperature, 185 °C; ramp at 25 °C/min to 240 °C; hold for 0.5 min; ramp at 5 °C/min to 250 °C, then 40 °C/min to 290 °C; hold for 1.0 min. The injection temperature was 260 °C, and the transfer line temperature was 290 °C. The following were obtained from Radian Corporation: (a) codeine, morphine, hydrocodone, hydromorphone, and oxycodone, which were used to prepare calibrators; (b) deuterated codeine, morphine, hydrocodone, and hydromorphone, which were used as internal standards; and (c) oxymorphone and norcodeine, which were used for interference …
- Published
- 2001
42. Urine drug testing of chronic pain patients. II. Prevalence patterns of prescription opiates and metabolites
- Author
-
Yale H. Caplan, Anne Zichterman, Tim Robert, Edward J. Cone, Frank Moser, Rebecca Heltsley, Beverly Cawthon, and David L. Black
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Substance-Related Disorders ,Health, Toxicology and Mutagenesis ,Pain ,Enzyme-Linked Immunosorbent Assay ,Pharmacology ,Toxicology ,Drug Prescriptions ,Analytical Chemistry ,Norcodeine ,Tandem Mass Spectrometry ,medicine ,Environmental Chemistry ,Humans ,Chromatography, High Pressure Liquid ,Morphine Derivatives ,Chemical Health and Safety ,Chromatography ,Chemistry ,Codeine ,Norhydrocodone ,Dihydrocodeine ,Analgesics, Opioid ,Substance Abuse Detection ,Oxymorphone ,Chronic Disease ,Morphine ,Pain Clinics ,Opiate ,Oxycodone ,medicine.drug - Abstract
This study of 20,089 urine specimens from chronic pain patients provided a unique opportunity to evaluate the prevalence of prescription opiates and metabolites, assess the usefulness of inclusion of normetabolites in the test panel, and compare opiate and oxycodone screening results to liquid chromatography with tandem mass spectrometry (LC-MS-MS) results. All specimens were screened by an opiate [enzyme-linked immunosorbent assay (ELISA), 100 ng/mL] and oxycodone assay [ELISA, 100 ng/mL or enzyme immunoassay (EIA), 50 ng/mL] and simultaneously tested by LC-MS-MS [limit of quantitation (LOQ) = 50 ng/mL] for 10 opiate analytes (codeine, norcodeine, morphine, hydrocodone, dihydrocodeine, norhydrocodone, hydromorphone, oxycodone, noroxycodone, and oxymorphone). Approximately two-thirds of the specimens were positive for one or more opiate analytes. The number of analytes detected in each specimen varied from 1 to 8 with 3 (34.8%) being most prevalent. Hydrocodone and oxycodone (in combination with metabolites) were most prevalent followed by morphine. Norcodeine was only infrequently detected whereas the prevalence of norhydrocodone and noroxycodone was approximately equal to the prevalence of the parent drug. A substantial number of specimens were identified that contained norhydrocodone (n = 943) or noroxycodone (n = 702) but not the parent drug, thereby establishing their interpretative value as biomarkers of parent drug use. Comparison of the two oxycodone screening assays revealed that the oxycodone ELISA had broader cross-reactivity with opiate analytes, and the oxycodone EIA was more specific for oxycodone. Specimens containing only norhydrocodone were best detected with the opiate ELISA whereas noroxycodone (only) specimens were best detected by the oxycodone EIA.
- Published
- 2010
43. Identification and quantitation of amphetamines, cocaine, opiates, and phencyclidine in oral fluid by liquid chromatography-tandem mass spectrometry
- Author
-
Dean Fritch, Kristen Blum, Sheena Nonnemacher, Matthew P. Sullivan, Brenda J. Haggerty, and Edward J. Cone
- Subjects
Health, Toxicology and Mutagenesis ,Phencyclidine ,Ion suppression in liquid chromatography–mass spectrometry ,Toxicology ,Sensitivity and Specificity ,Analytical Chemistry ,Matrix (chemical analysis) ,chemistry.chemical_compound ,Norcodeine ,Cocaine ,Liquid chromatography–mass spectrometry ,Predictive Value of Tests ,Tandem Mass Spectrometry ,medicine ,Environmental Chemistry ,Humans ,Solid phase extraction ,Saliva ,Automation, Laboratory ,Chemical Health and Safety ,Chromatography ,Chemistry ,Amphetamines ,Reproducibility of Results ,Norhydrocodone ,Dihydrocodeine ,Analgesics, Opioid ,Substance Abuse Detection ,Calibration ,Benzoylecgonine ,medicine.drug ,Chromatography, Liquid - Abstract
Analytical methods for measuring multiple licit and illicit drugs and metabolites in oral fluid require high sensitivity, specificity, and accuracy. With the limited volume available for testing, comprehensive methodology is needed for simultaneous measurement of multiple analytes in a single aliquot. This report describes the validation of a semi-automated method for the simultaneous extraction, identification, and quantitation of 21 analytes in a single oral fluid aliquot. The target compounds included are amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxy-amphetamine, 3,4-methylenedioxyethylamphetamine, pseudoephedrine, cocaine, benzoylecgonine, codeine, norcodeine, 6-acetylcodeine, morphine, 6-acetylmorphine, hydrocodone, norhydrocodone, dihydrocodeine, hydromorphone, oxycodone, noroxycodone, oxymorphone, and phencyclidine. Oral fluid specimens were collected with the Intercept device and extracted by solid-phase extraction (SPE). Drug recovery from the Intercept device averaged 84.3%, and SPE extraction efficiency averaged 91.2% for the 21 analytes. Drug analysis was performed by liquid chromatography-tandem mass spectrometry in the positive electrospray mode using ratios of qualifying product ions within +/-25% of calibration standards. Matrix ion suppression ranged from -57 to 8%. The limit of quantitation ranged from 0.4 to 5 ng/mL using 0.2 mL of diluted oral fluid sample. Application of the method was demonstrated by testing oral fluid specimens from drug abuse treatment patients. Thirty-nine patients tested positive for various combinations of licit and illicit drugs and metabolites. In conclusion, this validated method is suitable for simultaneous measurement of 21 licit and illicit drugs and metabolites in oral fluid.
- Published
- 2009
44. Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electrochemical detection
- Author
-
C.P.W.G.M. Verwey-van Wissen, Tom B. Vree, and P.M. Koopman-Kimenai
- Subjects
Normorphine ,Morphine Derivatives ,Chromatography ,Morphine ,Codeine ,Hydrolysis ,Metabolite ,Reproducibility of Results ,Glucuronates ,General Chemistry ,High-performance liquid chromatography ,Glucuronidase ,chemistry.chemical_compound ,Norcodeine ,chemistry ,Electrochemistry ,medicine ,Humans ,Glucuronide ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
A high-performance liquid chromatographic method has been developed for the detection, separation and measurement of codeine and its metabolites norcodeine, morphine and normorphine, with their glucuronide conjugates. The glucuronidase Escherichia coli type VIIA hydrolyses codeine-6-glucuronide completely and is used for the construction of the calibration curves of codeine-6-glucuronide. Enzymic hydrolysis of codeine-6-glucuronide depends on the specific activity of the glucuronidase applied. Examples are shown of a volunteer who is able to form morphine from codeine and one who is unable to do so.
- Published
- 1991
45. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine
- Author
-
Jan Svensson, Q. Y. Yue, Jan Hasselström, and Juliette Säwe
- Subjects
Adult ,Male ,Glucuronidation ,Administration, Oral ,Codeine Phosphate ,Pharmacology ,Hydroxylation ,White People ,chemistry.chemical_compound ,Norcodeine ,Pharmacokinetics ,Reference Values ,medicine ,Humans ,Pharmacology (medical) ,Active metabolite ,Normorphine ,Codeine ,Chemistry ,Area under the curve ,Middle Aged ,Debrisoquin ,Phenotype ,Debrisoquine ,Female ,Research Article ,Half-Life ,medicine.drug - Abstract
1. The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2. The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 +/- 340 nmol l-1 h, 2.58 +/- 0.57 h and 2.02 +/- 0.73 l h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3. PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P less than 0.0001), and lower partial metabolic clearance by O-demethylation (P less than 0.0001). In contrast, the PM had higher AUC of NC (P less than 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4. Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N- and O-demethylations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1991
46. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine
- Author
-
Folke Sjöqvist, Jan Svensson, Q. Y. Yue, and Juliette Säwe
- Subjects
Adult ,Male ,Debrisoquin ,Glucuronidation ,Cmax ,Administration, Oral ,Codeine Phosphate ,Pharmacology ,White People ,chemistry.chemical_compound ,Norcodeine ,Asian People ,Reference Values ,medicine ,Humans ,Pharmacology (medical) ,Chromatography, High Pressure Liquid ,Codeine ,Middle Aged ,Phenotype ,Debrisoquine ,chemistry ,Morphine ,Female ,Research Article ,medicine.drug - Abstract
1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l-1) and AUC (1660 nmol l-1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l-1 and 1010 nmol l-1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half-life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/- 0.14 s.d. vs 1.42 +/- 0.48 s.d. 1 h-1 kg-1) in Chinese than in Caucasians. 4. The total urinary recovery of drug-related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6-glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.
- Published
- 1991
47. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers
- Author
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G. Reynolds, Z. R. Chen, Felix Bochner, and Andrew A. Somogyi
- Subjects
Male ,Pharmacology ,Codeine ,Metabolic Clearance Rate ,Reabsorption ,Chemistry ,Kidney metabolism ,Dextromethorphan ,Middle Aged ,Kidney ,Norcodeine ,Pharmacokinetics ,Renal physiology ,medicine ,Morphine ,Humans ,Female ,Pharmacology (medical) ,Aged ,Research Article ,medicine.drug - Abstract
1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1991
48. High throughput screening various abused drugs and metabolites in urine by liquid chromatography-heated electrospray ionization/tandem mass spectrometry
- Author
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Tzung-Jie Yang, Chung-Yu Chen, Yan-Zin Chang, Maw-Rong Lee, and Chien-Chun Shen
- Subjects
Electrospray ,Spectrometry, Mass, Electrospray Ionization ,Time Factors ,Formates ,Electrospray ionization ,Drug Evaluation, Preclinical ,Urine ,Acetates ,Urinalysis ,Tandem mass spectrometry ,Analytical Chemistry ,Norcodeine ,Tandem Mass Spectrometry ,medicine ,Humans ,Detection limit ,Chemical ionization ,Chromatography ,Chemistry ,Illicit Drugs ,Methanol ,Amphetamines ,Reproducibility of Results ,Ketamine ,Gas chromatography–mass spectrometry ,medicine.drug ,Chromatography, Liquid - Abstract
An integrated method of liquid chromatography–heated electrospray ionization/tandem mass spectrometry was evaluated for high throughput screening of various abused drugs in urine. Chromatographic analysis was performed on a C18 reverse phase column using a linear gradient of 10 mM ammonium acetate containing 0.1% formic acid–methanol as mobile phase and the total separation time was 7 min. A simple and rapid sample preparation method used was by passing urine samples through a 0.22 μm PVDF syringe filter. The detection limits of the studied abused drugs in urine were from 0.6 ng mL−1 (ketamine) to 9.0 ng mL−1 (norcodeine). According to the results, the linear range was from 1 to 1200 ng mL−1 with relative standard deviation (R.S.D.s) value below 14.8% (intra-day) and 24.6% (inter-day). The feasibility of applying the proposed method to determine various abused drugs in real samples was examined by analyzing urine samples from drug-abused suspects. The abused drugs including ketamines and amphetamines were detected in suspected urine samples. The results demonstrate the suitability of LC–HESI-MS/MS for high throughput screening of the various abused drugs in urine.
- Published
- 2008
49. Species differences in metabolism of codeine: urinary excretion of codeine glucuronide, morphine-3-glucuronide and morphine-6-glucuronide in mice, rats, guinea pigs and rabbits
- Author
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Hidetoshi Yoshimura, Kazuta Oguri, and Nobumitsu Hanioka
- Subjects
Male ,Health, Toxicology and Mutagenesis ,Guinea Pigs ,Analgesic ,Glucuronidation ,Pharmacology ,Toxicology ,Biochemistry ,Mice ,chemistry.chemical_compound ,Norcodeine ,Species Specificity ,medicine ,Animals ,Chromatography, High Pressure Liquid ,Morphine-3-glucuronide ,Morphine Derivatives ,Morphine ,Codeine ,Chemistry ,Rats, Inbred Strains ,General Medicine ,Morphine-6-glucuronide ,Rats ,Rabbits ,Glucuronide ,medicine.drug - Abstract
1. Metabolites of codeine were determined by use of h.p.l.c. in urine of male mice, rats, guinea pigs and rabbits injected with 10 mg codeine/kg subcutaneously. 2. In 24 h urines of these species, unchanged codeine, codeine glucuronide, free morphine, and morphine-3-glucuronide were as follows: mice, 6.8, 1.6, 0.8 and 7.6% dose; rats, 1.6, 0.2, 4.3 and 23.9% dose; guinea pigs, 1.6, 39.8, 0.2 and 1.6% dose; rabbits, 2.2, 24.5, 1.3 and 17.9% dose. Urinary excretion of morphine-6-glucuronide was 0.7% dose in guinea pigs, 1.9% in rabbits, and not detectable in mice and rats. Norcodeine was found only in the urine of mice. 3. These results indicate that codeine is metabolized in all four species by glucuronidation and by oxidative N- and O-demethylation, but the quantitative excretions of metabolites were quite different in different species.
- Published
- 1990
50. Determination of morphine and codeine in urine by gas chromatography—mass spectrometry
- Author
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A. Solans, Jordi Segura, and R. de la Torre
- Subjects
Trimethylsilyl Compounds ,Clinical Biochemistry ,Pharmaceutical Science ,Urine ,Mass spectrometry ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,chemistry.chemical_compound ,Norcodeine ,Drug Discovery ,medicine ,Humans ,Solid phase extraction ,Spectroscopy ,Immunoassay ,Normorphine ,Morphine Derivatives ,Chromatography ,Morphine ,Codeine ,Hydrolysis ,chemistry ,Indicators and Reagents ,6-Monoacetylmorphine ,Gas chromatography–mass spectrometry ,medicine.drug - Abstract
GC-MS is one of the recommended analytical techniques for the identification and confirmation of opiates in urine. A method for the qualitative detection and quantitation of codeine and morphine in urine samples by this technique has been developed. This method is also suitable for the detection of their main metabolites in urine: norcodeine and normorphine. It also allows the identification of 6-monoacetylmorphine in urine, which can be used as a confirmatory marker of heroine abuse. The derivatized compounds are separated by capillary gas chromatography (GC) and identified by mass spectrometry (MS) in the selective ion monitoring acquisition mode (SIM). The recoveries from urine at concentrations of 1000 ng ml-1 are 72% for codeine and 80% for morphine. The method is linear in the range studied (0-1000 ng ml-1) for codeine and morphine.
- Published
- 1990
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