79 results on '"Norcodeine"'
Search Results
2. Breaking the Codeine : Fatal Forty DDI: codeine, quinidine, CYP2D6
- Author
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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. 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
9. 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
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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
10. 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.
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- 2018
11. 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
12. 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
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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
13. Urine testing for norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives
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Beverly Cawthon, Yale H. Caplan, Frank Moser, Rebecca Heltsley, Tim Robert, Anne Zichterman, Edward J. Cone, and David L. Black
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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
14. Bioconversion of codeine to semi-synthetic opiate derivatives by the cyanobacterium Nostoc muscorum
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Somayeh Niknam, Mojtaba Tabatabaei Yazdi, Mohammad Ali Faramarzi, Hossein Rastegar, Khosrou Abdi, and Mohsen Amini
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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
15. Determination of medicinal and illicit drugs in post mortem dental hard tissues and comparison with analytical results for body fluids and hair samples
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Markus Jörg Altenburger, Jürgen Kempf, Merja A. Neukamm, Volker Auwärter, and Miriam Klima
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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
16. Breaking the Codeine
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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
17. Codeine Can’t Do It
- Author
-
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
18. Solid-state IR-LD spectroscopy of codeine and N-norcodeine derivatives
- Author
-
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
19. 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
20. Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes
- Author
-
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
21. Effects of Ethanol on Ethylmorphine Metabolism in Isolated Rat Hepatocytes: Characterization by Means of a Multicompartmental Model
- Author
-
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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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
29. 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
30. 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
31. 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
32. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers
- Author
-
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
33. 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
-
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
34. Determination of morphine and codeine in urine by gas chromatography—mass spectrometry
- Author
-
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
35. Opioid disposition in human sweat after controlled oral codeine administration
- Author
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Edward J. Cone, Allan J. Barnes, Eric T. Moolchan, Marilyn A. Huestis, Eugene W. Schwilke, and Sherri L. Kacinko
- Subjects
Adult ,Male ,Narcotics ,Time Factors ,Clinical Biochemistry ,Administration, Oral ,Pharmacology ,Gas Chromatography-Mass Spectrometry ,Excretion ,SWEAT ,Norcodeine ,Oral administration ,Medicine ,Humans ,Sweat ,Normorphine ,business.industry ,Codeine ,Biochemistry (medical) ,Reproducibility of Results ,Substance Abuse Detection ,Opioid ,Morphine ,Female ,business ,medicine.drug - Abstract
Background: Characterization of opioid excretion in sweat is important for accurate interpretation of sweat tests in drug treatment, criminal justice, and workplace drug testing programs.Methods: Participants (n = 20) received placebo, 3 low (60 mg/70 kg) or 3 high (120 mg/70 kg) codeine sulfate doses (used as a model for opioid excretion) within 1 week. Codeine and metabolites in sweat were collected with PharmChek® Sweat Patches; hourly patches were applied for 1 to 15 h (n = 775) and weekly patches for 7 days (n = 118). Patches were analyzed by solid-phase extraction and gas chromatography–mass spectrometry for codeine, norcodeine, morphine, normorphine, and 6-acetylmorphine. Limits of quantification were 2.5 ng/patch (codeine and morphine) and 5 ng/patch (other analytes).Results: Codeine was the only analyte identified in 12.6% of hourly patches and 83.3% of weekly sweat patches worn during dosing. Weekly patch concentrations (SD) were 38.6 (59.9) ng/patch [median (range), 15.9 (0–225.1) ng/patch] for low and 34.1 (32.7) ng/patch [24.0 (0–96.2) ng/patch] for high codeine doses. Codeine detected 1 week after dosing was 4.6 (5.3) ng/patch [median (range), 4.0 (0–17.1) ng/patch; n = 11] after low and 7.7 (7.1) ng/patch [6.9 (0–20.5) ng/patch; n = 10] after high doses. In total, 2.6% of hourly, 38.5% of low-dose, and 45.5% of high-dose weekly patches contained codeine at the proposed Substance Abuse and Mental Health Services Administration cutoff.Conclusions: Codeine was the only analyte detected, at highly variable concentrations, up to 2 weeks after dosing. These results are consistent, considering the complex processes of codeine deposition in sweat. Sweat testing is a useful alternative technique for qualitative monitoring of opioid use.
- Published
- 2006
36. Direct analysis of opiates in urine by liquid chromatography-tandem mass spectrometry
- Author
-
Ronald C. Backer, Alphonse Poklis, and Leslie E. Edinboro
- Subjects
Narcotics ,Spectrometry, Mass, Electrospray Ionization ,Health, Toxicology and Mutagenesis ,Electrospray ionization ,Urine ,Toxicology ,Mass spectrometry ,High-performance liquid chromatography ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,Norcodeine ,Glucuronides ,Liquid chromatography–mass spectrometry ,medicine ,Environmental Chemistry ,Humans ,Chromatography, High Pressure Liquid ,Chemical Health and Safety ,Chromatography ,Chemistry ,Codeine ,Reproducibility of Results ,Opioid-Related Disorders ,Substance Abuse Detection ,Opiate ,medicine.drug - Abstract
I A method for the direct analysis of 10 opiate compounds in urine was developed using liquid chromatography-mass spectrometry-mass spectrometry (LC-MS--MS) with electrospray ionization interface (ESI). Opiates included were morphine-3-~- glucuronide, morphine-6-~glucuronide, morphine, oxymorphone, hydromorphone, norcodeine, codeine, oxycodone, 6-monoacetylmorphine (6MAM), and hydrocodone. Urine samples were prepared by centrifugation to remove large particles and direct injection into the LC-MS-MS. Separation and detection of all compounds was accomplished within 6 rain. Linearity was established for all opiates except 6MAM from 50 ng/mL to 10,000 ng/mt; 6MAM from 0.25 ng/mt to 50 ng/mL with all correlation coefficients (r) > 0.99. Interrun precision (%CV) ranged from 1.1 % to 16.7%, and intrarun precision ranged from 1.3% to 16.3%. Accuracy (% bias) ranged from -7.3% to 13.6% and -8.5 % to l ! .8 for inter- and intrarun, respectively. Eighty-nine urine samples previously analyzed by gas chromatography-MS were re-analyzed by the LC-MS-MS method. The qualitative results found an 88% agreement for negative samples between the two methods and 94% for positive samples. The LC-MS-MS method identified 19 samples with additional opiates in the positive samples. Overall, the direct injection LC-MS-MS method performed well and permitted the rapid analysis of urine samples for several opiates simultaneously without extensive sample preparation.
- Published
- 2006
37. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites
- Author
-
Jörn Lötsch, Maren Rohrbacher, Gerd Geisslinger, Carsten Skarke, Matthias Schwab, Ute Hofmann, and Helmut Schmidt
- Subjects
Adult ,Central Nervous System ,Male ,Metabolite ,Pharmacology ,chemistry.chemical_compound ,Norcodeine ,Oral administration ,medicine ,Humans ,Pharmacology (medical) ,Infusions, Intravenous ,Normorphine ,Morphine Derivatives ,Models, Statistical ,Morphine ,Codeine ,Area under the curve ,Pupil ,Analgesics, Opioid ,Opioid ,chemistry ,Cytochrome P-450 CYP2D6 ,Dealkylation ,Area Under Curve ,Data Interpretation, Statistical ,Female ,Algorithms ,medicine.drug - Abstract
Objective Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6–mediated O-demethylation to morphine. Methods After oral administration of codeine, plasma concentrations of codeine and its metabolites, as well as pupil size as a measure of central nervous effects, were measured in 11 healthy volunteers representing poor, intermediate, extensive, and ultrarapid metabolizers for CYP2D6. Subsequently, the observed plasma morphine concentrations were mimicked by use of computerized morphine infusion, and the miotic effects were compared with those observed after codeine administration. The contribution of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-6-glucuronide, and normorphine to the miotic effects was analyzed by means of pharmacokinetic-pharmacodynamic modeling. Results The areas under the curve of the miotic effects after codeine were 1.7±2 times greater than after morphine (P
- Published
- 2005
38. A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine
- Author
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Michael R. Boyd, Shankar J. Chinta, Reddy P. Kommaddi, Toshiyuki Mori, Vijayalakshmi Ravindranath, and Harish V. Pai
- Subjects
Molecular Sequence Data ,Receptors, Opioid, mu ,Gene Expression ,Drug action ,Biology ,Kidney ,Biochemistry ,Methylation ,Frameshift mutation ,Mice ,Norcodeine ,Cytochrome P-450 Enzyme System ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Frameshift Mutation ,Molecular Biology ,Base Sequence ,Morphine ,Codeine ,Alternative splicing ,Intron ,Brain ,Cell Biology ,Human brain ,Molecular biology ,Recombinant Proteins ,Isoenzymes ,Alternative Splicing ,medicine.anatomical_structure ,Opioid ,Cytochrome P-450 CYP2D6 ,Genes ,Liver ,Drug metabolism ,Pseudogenes ,medicine.drug - Abstract
A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to micro-opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and micro-opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histio-specific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.
- Published
- 2004
39. Voltammetric Oxidation of Drugs of Abuse II. Codeine and Metabolites
- Author
-
Garrido, Jorge, Delerue-Matos, Cristina, Borges, F., Macedo, Tice R. A., Oliveira-Brett, A. M., and Repositório Científico do Instituto Politécnico do Porto
- Subjects
Drugs of abuse ,Codeine ,Acetylcodeine ,Oxidation ,Electrochemistry ,Voltammetry ,Norcodeine ,Dihydrocodeine ,Codeine-N-oxide ,Analytical Chemistry ,6-Chlorodesoxycodeine - Abstract
The oxidation of codeine on glassy carbon electrodes has been studied in detail using differential pulse voltammetry. The results obtained using a glassy carbon electrode clearly show a much more complex oxidation mechanism than that previously reported when platinum and gold electrodes were used. To clarify the codeine oxidative profile, several metabolites and analogues of this alkaloid, codeine N-oxide, norcodeine, dihydrocodeine, acetylcodeine and 6- chlorodesoxycodeine, were synthesized and studied. It was deduced that the anodic waves observed in codeine oxidation are related to the presence of methoxy, hydroxy and tertiary amine groups. Due to the similarity of potentials at which these oxidative processes take place, at some pHs an overlap of peaks occurs and only one anodic wave is observed.
- Published
- 2004
40. Sensitivity, specificity, and efficiency in detecting opiates in oral fluid with the Cozart Opiate Microplate EIA and GC-MS following controlled codeine administration
- Author
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Gail Cooper, Claire Reid, Allan J. Barnes, Insook Kim, Marilyn A. Huestis, Raf Schepers, Lisa Wilson, Chris Hand, and Eric T. Moolchan
- Subjects
Male ,medicine.medical_specialty ,Saliva ,Health, Toxicology and Mutagenesis ,Administration, Oral ,Enzyme-Linked Immunosorbent Assay ,Toxicology ,Gastroenterology ,Sensitivity and Specificity ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,Microtiter plate ,Norcodeine ,Oral administration ,Internal medicine ,medicine ,Environmental Chemistry ,Humans ,Normorphine ,Chemical Health and Safety ,Chromatography ,Chemistry ,Codeine ,Opioid-Related Disorders ,Substance Abuse Detection ,Morphine ,Female ,Opiate ,medicine.drug - Abstract
Oral fluid specimens (N = 1406) were collected from 19 subjects prior to and up to 72 h following controlled administration of oral codeine. Volunteers provided informed consent to participate in this National Institute on Drug Abuse Institutional Review Board-approved protocol. A modification of Cozart Microplate Opiate EIA Oral Fluid Kit (Opiate ELISA), employing codeine calibrators, was used for semiquantitative analysis of opiates, followed by gas chromatography-mass spectrometry (GC-MS) for the confirmation and quantitation of codeine, norcodeine, morphine, and normorphine in oral fluid. GC-MS limits of detection and quantitation were 2.5 microg/L for all analytes. The Substance Abuse and Mental Health Services Administration (SAMHSA) has proposed a 40-microg/L opiate screening and a 40-microg/L morphine or codeine confirmation cutoff for the detection of opiate use. Oral fluid opiate screening and confirmation cutoffs of 30 micro g/L are in use in the U.K. Utilizing 2.5-, 20-, 30-, and 40-microg/L GC-MS cutoffs, 26%, 20%, 19%, and 18% of the oral fluid specimens were positive for codeine or one of its metabolites. Six Opiate ELISA/confirmation cutoff criteria (2.5/2.5, 10/2.5, 20/20, 30/20, 30/30, and 40/40 microg/L) were evaluated. Calculations for Opiate ELISA sensitivity, specificity, and efficiency were determined from the number of true-positive, true-negative, false-positive, and false-negative results at each screening/confirmation cutoff. Sensitivity, specificity, and efficiency for the lowest cutoff were 91.5%, 88.6%, and 89.3%. Application of the cutoff currently used in the U.K. yielded sensitivity, specificity, and efficiency results of 79.7%, 99.0%, and 95.4% and similar results of 76.7%, 99.1%, and 95.1% when applying the SAMHSA criteria. These data indicate that the Opiate ELISA efficiently detects oral codeine use. In addition, the data, collected following controlled oral codeine administration, may aid in the interpretation of opiate oral fluid test results and in the selection of appropriate oral fluid screening and confirmation cutoffs.
- Published
- 2003
41. Performance characteristics of the Cozart RapiScan Oral Fluid Drug Testing System for opiates in comparison to ELISA and GC/MS following controlled codeine administration
- Author
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Allan J. Barnes, Dene Baldwin, Gail Cooper, Lisa Wilson, Claire Reid, Chris Hand, Eric T. Moolchan, Insook Kim, Marilyn A. Huestis, and Sherri L. Kacinko
- Subjects
Enzyme-Linked Immunosorbent Assay ,Sensitivity and Specificity ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,Norcodeine ,Oral administration ,medicine ,Cutoff ,Drug test ,Humans ,False Positive Reactions ,Saliva ,False Negative Reactions ,Normorphine ,Chromatography ,medicine.diagnostic_test ,business.industry ,Codeine ,Forensic Medicine ,Analgesics, Opioid ,Substance Abuse Detection ,Morphine ,Opiate ,business ,Law ,medicine.drug - Abstract
Oral fluid is an interesting alternative matrix for drug testing in many environments, including law enforcement, workplace drug testing, and drug treatment facilities. Performance characteristics of the FDA-cleared, qualitative, Cozart RapiScan Opiate Oral Fluid Drug Testing System (Opiate Cozart RapiScan System or Opiate CRS) were compared to the semi-quantitative Cozart Microplate EIA Opiate Oral Fluid Kit (Opiate ELISA) and to gas chromatography/mass spectrometry (GC/MS). The following oral fluid opiate cutoffs were evaluated: the GC/MS limit of quantification (LOQ) of 2.5 mg/l; 15 microg/l currently used for oral fluid testing in the United Kingdom (UK); 30 microg/l (Opiate CRS cutoff); and 40 microg/l, the proposed Substance Abuse and Mental Health Services Administration (SAMHSA) cutoff. Subjects provided informed consent to participate in this IRB-approved research and resided on the closed research ward throughout the study. Three oral codeine doses of 60 mg/70 kg were administered over a 7-day period. After a 3-week break, subjects received three doses of 120 mg/70 kg within 7 days. Oral fluid specimens (N = 1273) were analyzed for codeine (COD), norcodeine (NCOD), morphine (MOR) and normorphine (NMOR) by GC/MS with an LOQ of 2.5 microg/l for all analytes. MOR and NMOR were not detected in any sample; 26.5% of the specimens were positive for COD and 13.7% for NCOD. Opiate CRS uses a preset, qualitative cutoff of 10 microg/l; this is equivalent to 30 microg/l in undiluted oral fluid as the oral fluid collection process involves a 1:3 dilution with buffer. Sensitivity, specificity, and efficiency of Opiate CRS compared to Opiate ELISA were 98.6, 98.1, and 98.2% at a 30 microg/l cutoff and 99.0, 96.2, and 96.6% at a 40 microg/l cutoff. Compared to the much lower GC/MS LOQ of 2.5 microg/l, sensitivity, specificity and efficiency were 66.8, 99.3 and 90.7%. Increasing the GC/MS cutoff to the current UK level yielded performance characteristics of 81.5% (sensitivity), 99.3% (specificity), and 95.4% (efficiency). Using a GC/MS cutoff identical to the preset Opiate CRS cutoff yielded sensitivity, specificity, and efficiency of 88.5, 99.2, and 97.5%, respectively. At the proposed SAMSHA confirmation cutoff of 40 microg/l, sensitivity increased with little change in specificity and efficiency (91.3% sensitivity, 98.9% specificity, and 97.5% efficiency). Oral fluid is a suitable matrix for detecting drugs of abuse. Opiate CRS, with a 30 microg/l cutoff, is sufficiently sensitive, specific and efficient for oral fluid opiate analysis, performing similarly to Opiate ELISA at the same cutoff, and having performance characteristics91% when compared to GC/MS at the proposed SAMHSA cutoff.
- Published
- 2003
42. A rapid GC-MS method for the determination of dihydrocodeine, codeine, norcodeine, morphine, normorphine and 6-MAM in urine
- Author
-
C Meadway, Steve George, and R.A. Braithwaite
- Subjects
Adult ,Male ,Narcotics ,medicine.medical_specialty ,Adolescent ,Urine ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Norcodeine ,Internal medicine ,medicine ,Humans ,Normorphine ,Morphine Derivatives ,Chromatography ,Morphine ,Codeine ,Middle Aged ,Dihydrocodeine ,Endocrinology ,chemistry ,Female ,6-Monoacetylmorphine ,Opiate ,Law ,medicine.drug - Abstract
The presence of the heroin metabolite 6-monoacetylmorphine (6-MAM) in urine is used to definitively identify recent heroin abuse. A rapid and sensitive GC-MS method for the simultaneous analysis of codeine, norcodeine, morphine, normorphine and 6-MAM in urine was developed and successfully applied to the analysis of 321 'heroin-positive' urine specimens from individual subjects (identified by the presence of 6-MAM), to provide quantitative urinary opiate excretion data for heroin abusers. The cohort analysed was composed of 238 males (age range 16-53 years) and 83 females (age range 16-50 years). The concentrations of free 6-MAM, morphine and codeine determined in these 321 specimens ranged between 103-246,312, 129-193,600 and 103-519,000 microg/l, respectively. Free norcodeine and normorphine concentrations were found to range between 143-50,200 and 205-149,700 microg/l, respectively. A statistically significant relationship was determined between the subject age and the 6-MAM concentration, possibly indicating opiate tolerance in these individuals.
- Published
- 2002
43. Normorphine is the Major Metabolite of Norcodeine in Isolated Rat Hepatocytes
- Author
-
Asbjørg S. Christophersen, Egil Bodd, and Unni Fongen
- Subjects
Male ,Chromatography, Gas ,Metabolite ,Biology ,Toxicology ,High-performance liquid chromatography ,chemistry.chemical_compound ,Norcodeine ,medicine ,Animals ,Cells, Cultured ,Chromatography, High Pressure Liquid ,Pharmacology ,Normorphine ,Morphine Derivatives ,Chromatography ,Codeine ,Rats, Inbred Strains ,Metabolism ,In vitro ,Rats ,medicine.anatomical_structure ,Liver ,chemistry ,Biochemistry ,Hepatocyte ,Spectrophotometry, Ultraviolet ,medicine.drug - Published
- 2009
44. Fully automated analytical method for codeine quantification in human plasma using on-line solid-phase extraction and high-performance liquid chromatography with ultraviolet detection
- Author
-
Javier Sanagustı́n and José A Pascual
- Subjects
Detection limit ,Reproducibility ,Chromatography ,Chemistry ,Elution ,Codeine ,Analytical chemistry ,Reproducibility of Results ,General Chemistry ,High-performance liquid chromatography ,Sensitivity and Specificity ,Automation ,Norcodeine ,medicine ,Morphine ,Humans ,Spectrophotometry, Ultraviolet ,Solid phase extraction ,Quantitative analysis (chemistry) ,Chromatography, High Pressure Liquid ,medicine.drug - Abstract
A simple, sensitive and fully automated analytical method for the analysis of codeine in human plasma is presented. Samples are added with oxycodone, used as internal standard (I.S.), and directly loaded in the autosampler tray. An on-line sample clean-up system based on solid-phase extraction (SPE) cartridges (Bond-Elut C2, 20 mg) and value switching (Prospekt) is used. Isocratic elution improved reproducibility and allowed the recirculation of the mobile phase. A Hypersil BDS C18, 3 microns, 10 x 0.46 cm column was used and detection was done by UV monitoring at 212 nm. Retention times of norcodeine (codeine metabolite), codeine and oxycodone (I.S.) were 5.5, 6.4 and 9.1 min, respectively. Morphine was left to elute in the chromatographic front. Detection limit for codeine was 0.5 microgram l-1 and inter-assay precision (expressed as relative standard deviation) and accuracy (expressed as relative error) measured at 2 micrograms l-1 were 5.03% and 1.82%. Calibration range was 2-140 micrograms l-1.
- Published
- 1999
45. Opiate concentrations following the ingestion of poppy seed products--evidence for 'the poppy seed defence'
- Author
-
Claire Meadway, Steve George, and R.A. Braithwaite
- Subjects
Adult ,Male ,Narcotics ,food.ingredient ,Thebaine ,Administration, Oral ,Poppy seed ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,Norcodeine ,Animal science ,food ,Poppy ,Botany ,medicine ,Papaveraceae ,Humans ,Papaver ,Morphine Derivatives ,Plants, Medicinal ,biology ,Morphine ,business.industry ,Codeine ,biology.organism_classification ,Seeds ,Opiate ,business ,Law ,Food Analysis ,medicine.drug - Abstract
The universally accepted 300 ng/ml cut-off limit for opiate assays stated to be mandatory for all drug screening laboratories by the Substance Abuse and Mental Health Services Administration, has been questioned recently due to positive results being obtained following the ingestion of poppy seed containing food products. To establish the plausibility of the 'the poppy seed defence' the concentrations of codeine, norcodeine, morphine, normorphine and thebaine (a potential marker for seed ingestion) in several varieties of poppy seeds from different countries were quantified by GC-MS. The country of origin of the seed specimen analysed and the preparation of the seeds prior to their culinary use was found to influence the alkaloid concentration determined. The maximum morphine and codeine concentrations determined in the seeds were found to be 33.2 and 13.7 micrograms/g seed respectively. In addition, thebaine concentrations were found to vary with each seed sample analysed. Following the consumption of bread rolls (mean 0.76 g seed covering per roll) by four subjects, all urine specimens analysed produced negative results (using the Dade Bebring EMIT II opiate screening assay) with the exception of one subject (body weight 63.0 kg) who consumed two poppy seed rolls. In this subject opiate positive screening results were obtained for up to 6 h post ingestion with maximum urinary morphine and codeine concentrations of 832.0 ng/ml (@ 2-4 h post ingestion) and 47.9 ng/ml (@ 0-2 h post ingestion) respectively being achieved. Following the ingestion of poppy seed cake containing an average of 4.69 g of seed per slice by four individuals, opiate positive screening results were obtained for up to 24 h. In one subject (dose equivalent to 0.07 g poppy seed/kg body weight) maximum urinary morphine and codeine concentrations of 302.1 ng/ml (@ 0-2 h) and 83.8 ng/ml (@ 2-4 h) respectively were recorded. The elimination of thebaine was found to vary widely between individuals, therefore suggesting that its absence from a specimen is not necessarily indicative of opiate abuse. These findings demonstrate that the poppy seed defence could be used as an argument in medico-legal and employment medical cases. Great care should therefore be taken when interpreting the data produced when screening for opiates.
- Published
- 1998
46. The detection of acetylcodeine and 6-acetylmorphine in opiate positive urines
- Author
-
Alphonse Poklis and Carol L. O'Neal
- Subjects
Narcotics ,Urine ,Gas Chromatography-Mass Spectrometry ,Pathology and Forensic Medicine ,chemistry.chemical_compound ,Norcodeine ,mental disorders ,medicine ,Humans ,Solid phase extraction ,Morphine Derivatives ,Chromatography ,Morphine ,Chemistry ,Codeine ,Heroin Dependence ,Diacetylmorphine ,Reproducibility of Results ,Substance Abuse Detection ,6-Monoacetylmorphine ,Opiate ,Law ,Biomarkers ,medicine.drug - Abstract
Acetylcodeine (AC), an impurity of illicit heroin synthesis, was investigated as a urinary biomarker for detection of illicit heroin use. One hundred criminal justice urine specimens that had been confirmed positive by GC/MS for morphine at concentrations > 5000 ng/ml were analyzed for AC, 6-acetylmorphine (6AM), codeine, norcodeine and morphine. The GC/MS analysis was performed by solid phase extraction and derivatization with propionic anhydride. Total codeine and morphine concentrations were determined by acid hydrolysis and liquid/liquid extraction. AC was detected in 37 samples at concentrations ranging from 2 to 290 ng/ml (median, 11 ng/ml). 6AM was also present in these samples at concentrations ranging from 49 to 12 600 ng/ml (median, 740 ng/ml). Of the 63 specimens negative for AC, 36 were positive for 6AM at concentrations ranging from 12 to 4600 ng/ml (median, 124 ng/ml). When detected, the AC concentrations were an average of 2.2% (0.25 to 10.2%) of the 6AM concentrations. There was a positive relationship between AC concentrations and 6AM concentrations (r = 0.878). Due to its very low concentration in urine, AC was found to be a much less reliable biomarker for illicit heroin use than 6AM in workplace or criminal justice urine screening programs. However, AC detection could play an important role in determining if addicts in heroin maintenance programs are supplementing their supervised diacetylmorphine doses with illicit heroin.
- Published
- 1998
47. Determination of morphine in urine by solid-phase immunoextraction and high-performance liquid chromatography with electrochemical detection
- Author
-
M.F. Katmeh, P. Kwasowski, B.A. Rashid, G.W. Aherne, and D. Stevenson
- Subjects
Biochemistry ,High-performance liquid chromatography ,Analytical Chemistry ,Norcodeine ,medicine ,Electrochemistry ,Animals ,Humans ,Sample preparation ,Solid phase extraction ,Chromatography, High Pressure Liquid ,Normorphine ,Chromatography ,Sheep ,Morphine ,Chemistry ,Elution ,Immunochemistry ,Organic Chemistry ,Codeine ,General Medicine ,Hydrogen-Ion Concentration ,Analgesics, Opioid ,Spectrophotometry, Ultraviolet ,Quantitative analysis (chemistry) ,medicine.drug - Abstract
The analysis of morphine in biological fluids is of vital interest in monitoring opiate abuse and in drug abuse research. Although methods for analysis of morphine and its metabolites are well established, studies are still being carried out to improve sample preparation procedures as well as detection levels of morphine in biological samples. In this study, morphine-specific immunosorbents were developed to concentrate morphine prior to HPLC analysis. Urine (0.1 ml) was diluted 10-fold with phosphate-buffered saline, pH 7.4 (PBS), loaded onto a solid-phase immunoextraction column and washed with 15 ml PBS followed by elution with 2 ml of elution buffer (40% ethanol in PBS, pH 4). The eluted fraction was analysed for morphine by HPLC-electrochemical detection using a cyanopropyl (CN) analytical column with 25% acetonitrile in phosphate buffer-sodium lauryl sulphate, pH 2.4 as the mobile phase. Duration of the extraction procedure was approximately 40 min. Calibration graphs were linear from 100 ng ml-1 to 500 ng ml-1 in urine. The inter-assay R.S.D. was10% and the recovery of morphine from urine was98%. Immunocolumns demonstrated remarkably high specificity towards morphine showing minimal binding with other opiate metabolites such as codeine, normorphine, norcodeine, morphine-3-glucuronide, morphine-6-glucuronide.
- Published
- 1998
48. Urinary excretion of codeine, ethylmorphine, and their metabolites: relation to the CYP2D6 activity
- Author
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K. Hedenmalm, Rune Dahlqvist, Kerstin Granberg, Olav Spigset, and Margit Sundgren
- Subjects
Pharmacology ,Normorphine ,Adult ,Male ,Chemistry ,Codeine ,Metabolic Clearance Rate ,Urine ,Dextromethorphan ,Ethylmorphine ,Analgesics, Opioid ,Norcodeine ,Phenotype ,Cytochrome P-450 CYP2D6 ,medicine ,Morphine ,Humans ,Pharmacology (medical) ,Female ,Opiate ,medicine.drug - Abstract
The formation of morphine from codeine and ethylmorphine is mainly mediated by the polymorphic enzyme CYP2D6. The objective of this study was to investigate whether CYP2D6 poor metabolizers (PM) and CYP2D6 extensive metabolizers (EM) would respond differently during testing for opiate drugs of abuse in urine after intake of these drugs. Five PM and five EM of dextromethorphan were administered single oral doses of codeine (25 mg) and ethylmorphine (25 mg), and the urinary excretion of parent compounds and selected metabolites was observed for 72 hours. Analysis was performed with GC-MS after hydrolysis of the glucuronide conjugates. Selected urine samples were screened for the presence of opiates by the Abbott ADx immunoassay method. The results from one PM and one EM were excluded because of technical analytical problems. EM excreted significantly more morphine than PM after intake of both codeine (6.5% vs. 1.1% of the dose; p < 0.05) and ethylmorphine (11.0% vs. 3.0% of the dose; p < 0.05). Screening results were positive significantly longer for EM than for PM after codeine intake (mean, 33 hours vs. 17 hours; p < 0.05), and the same trend, albeit nonsignificantly, was noted for ethylmorphine (mean, 33 hours vs. 24 hours). Regardless of CYP2D6 phenotype, significantly more morphine was formed after intake of ethylmorphine than after intake of codeine (7.0% vs. 3.8% of the dose; p < 0.05). There were high correlations between dextromethorphan metabolic ratios and the ratios of codeine to morphine, ethylmorphine to morphine, norcodeine to normorphine, and norethylmorphine to normorphine (r = 0.80 to 0.92; p = 0.030 to 0.001). Although this study should be interpreted with caution because of the few subjects included and the single-dose design, it demonstrates that the CYP2D6 phenotype clearly affects the results when testing for opiates in urine after intake of codeine and ethylmorphine.
- Published
- 1998
49. Evidence for CYP2D1-mediated primary and secondary O-dealkylation of ethylmorphine and codeine in rat liver microsomes
- Author
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Bang Qian Xu, Anders Bjørneboe, Asbjørg S. Christophersen, Jørg Mørland, and Tor A. Aasmundstad
- Subjects
Male ,Narcotics ,Metabolite ,Biochemistry ,chemistry.chemical_compound ,Norcodeine ,Cytochrome P-450 CYP2D6 Inhibitors ,medicine ,Animals ,Ethylmorphine ,heterocyclic compounds ,Troleandomycin ,Rats, Wistar ,Pharmacology ,Normorphine ,biology ,Codeine ,Cytochrome P450 ,Molecular biology ,Rats ,chemistry ,Cytochrome P-450 CYP2D6 ,Enzyme inhibitor ,Dealkylation ,biology.protein ,Microsome ,Microsomes, Liver ,Female ,Rabbits ,medicine.drug - Abstract
The purpose of the present study was to investigate the role of specific CYPs responsible for the O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M), as well as that of norethylmorphine (NEM) and norcodeine (NCD) to normorphine (NM) in rat liver microsomes. Liver microsomes metabolize EM and CD to M, and NEM and NCD to NM, in the presence of an NADPH-generating system. The metabolites of EM and CD were determined by HPLC with UV and electrochemical detection. In the present study, the role of CYP2D1 in O-dealkylation of EM/NEM and CD/NCD was investigated by use of specific antiCYP antibodies. When testing rabbit antirat CYP2D1, 2E1, 2C11, and 3A2 antibodies, only the antiCYP2D1 antibody inhibited the EM/NEM and CD/NCD O-dealkylase activities significantly. The maximum inhibition achieved was approximately 80% at a protein ratio (IgG to microsomes) of 10:1, p = 0.001. The contribution of CYP2D1 to the O-dealkylation of EM/NEM and CD/NCD was further confirmed by use of the specific CYP2D1 inhibitors quinine and propafenone. Five microM of quinine inhibited the EM/NEM and CD/NCD O-dealkylase activities by approximately 80%. The CYP3A inhibitor troleandomycin (TAO) failed to inhibit the CYP2D1 catalyzed reaction, but did inhibit the N-demethylation of EM and CD. The O-dealkylation of NEM and NCD was also impaired in Dark Agouti rat (DA) liver microsomes. Taken together, the immunoinhibition and chemical-inhibitor studies of rat liver microsomes provided convincing evidence for the involvement of CYP2D1, the rat counterpart of human CYP2D6, in the metabolism of EM/NEM and CD/NCD to the corresponding O-dealkylated metabolites.
- Published
- 1997
50. Urine and plasma pharmacokinetics of codeine in healthy volunteers: implications for drugs-of-abuse testing
- Author
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Pierre Lafolie, Zhen Lin, Olof Beck, Freidoun Albertioni, and Lars O. Boreus
- Subjects
Adult ,Male ,Narcotics ,Health, Toxicology and Mutagenesis ,Analgesic ,Administration, Oral ,Urine ,Toxicology ,Analytical Chemistry ,Norcodeine ,Pharmacokinetics ,Blood plasma ,medicine ,Environmental Chemistry ,Humans ,Morphine Derivatives ,Chemical Health and Safety ,Chromatography ,Morphine ,Chemistry ,Codeine ,Half-life ,Middle Aged ,Substance Abuse Detection ,Female ,medicine.drug ,Half-Life - Abstract
Thirteen healthy volunteers participating in an open and randomized study received two single doses (25 and 50 mg) of codeine orally two weeks apart. Urine concentrations of opiates were studied for 96 h, and plasma concentrations of codeine and the metabolites codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were monitored for 24 h. Plasma was analyzed by high-performance liquid chromatography. Measurements of urine were made with the EMIT opiate-screening assay and with gas chromatography-mass spectrometry for total (conjugates liberated by acid hydrolysis) codeine, morphine, and norcodeine. In urine, the ratio between total recovered morphine and codeine as expressed in percent ranged from 2.3 to 23.3% with a mean value of 9.8%. This ratio increased with time, and, in all but three subjects, rose to greater than 1 after 22-36 h. In 58% of cases, this occurred within the detection time in the EMIT assay. The detection time in the EMIT screening assay was found to be 20-39 h after the 25-mg dose and 30-52 h after the 50-mg dose. Elimination rates calculated from urine data corrected for creatinine concentration showed that morphine was eliminated more slowly than codeine. In plasma, the highest concentrations and area-under-curve values were observed for C6G, followed by codeine and M3G. All compounds had peak plasma values 1-2 h after dosing. The elimination of M3G was slower than that of C6G. We concluded that the relative proportion of codeine and morphine varies both between individuals and as a function of time and that morphine may be present in concentrations above those of codeine even after moderate and single doses of codeine. This must be taken into consideration when interpreting the presence of opiates during drugs-of-abuse testing.
- Published
- 1996
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