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Alastair J. J. Wood - One of the best experts on this subject based on the ideXlab platform.
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Simultaneous determination of codeine and it seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection
Journal of Chromatography B: Biomedical Sciences and Applications, 1998Co-Authors: Huaibing He, Sheila Shay, Yoseph Caraco, Margaret Wood, Alastair J. J. WoodAbstract: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 C 18 cartridges and separated on a reversed-phase C 8 column with a mobile phase consisting of 77% buffer (5 m M sodium phosphate monobasic and 0.70 m M 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.
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Simultaneous determination of codeine and its seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection.
Journal of chromatography. B Biomedical sciences and applications, 1998Co-Authors: Huaibing He, Yoseph Caraco, Margaret Wood, S D Shay, Alastair J. J. WoodAbstract: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.
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pharmacogenetic determinants of codeine induction by rifampin the impact on codeine s respiratory psychomotor and miotic effects
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Yoseph Caraco, James R Sheller, Alastair J. J. WoodAbstract:Our objective was to examine the effect of rifampin on codeine’s pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of Norcodeine, Norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine’s respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine’s respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced—and hence codeine’s pharmacodynamic effects were attenuated—in EMs of debrisoquin.
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Pharmacogenetic Determinants of Codeine Induction by Rifampin: The Impact on Codeine’s Respiratory, Psychomotor and Miotic Effects
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Yoseph Caraco, James R Sheller, Alastair J. J. WoodAbstract:Our objective was to examine the effect of rifampin on codeine’s pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of Norcodeine, Norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine’s respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine’s respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced—and hence codeine’s pharmacodynamic effects were attenuated—in EMs of debrisoquin.
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Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity.
Drug Metabolism and Disposition, 1996Co-Authors: Yoseph Caraco, Tomonori Tateishi, F. P. Guengerich, Alastair J. J. WoodAbstract:Codeine is metabolized by glucuronidation, by O-demethylation to morphine, and by N-demethylation to Norcodeine. The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome P4502D6 (CYP2D6). The purpose of the present study was to identify the specific P450 enzyme responsible for codeine N-demethylation. Microsomal preparations (250 pmol of P450) obtained from 12 human liver donors were incubated with 20 microM codeine and analyzed for Norcodeine formation. Codeine N-demethylation activity was linearly correlated with nifedipine oxidation activity (r = 0.90, p < 0.001), a marker of CYP3A4, but not with codeine O-demethylation, a marker of CYP2D6. Preincubation with troleandomycin (50 microM), or gestodene (50 microM) inhibitors of CYP3A4, decreased the rate of production of Norcodeine by 60 and 45% compared to control values, respectively. Similarly, ketoconazole (10 microM) and erythromycin (10 microM) inhibited codeine N-demethylation by 75 and 35%, respectively. In contrast, the presence of quinidine, sulfaphenazole, or diethyldithiocarbamate in the incubation mixture had no effect on Norcodeine formation. Preincubation with antibodies raised to CYP3A4 (5 mg lgG/nmol P450) caused 96% inhibition of Norcodeine production, whereas preimmune IgG or antibodies raised to CYP2A6 and CYP2C had no effect. Additionally, significant Norcodeine production was observed with purified CYP3A4 derived from human liver microsomes. In conclusion, codeine N-demethylation activity cosegregates with CYP3A4 activity. Coadministration of codeine with selective inhibitors of CYP3A4 may result in increased morphine production and enhanced pharmacodynamic effects due to shunting down the CYP2D6 pathway.
Lars Slørdal - One of the best experts on this subject based on the ideXlab platform.
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post mortem levels and tissue distribution of codeine codeine 6 glucuronide Norcodeine morphine and morphine glucuronides in a series of codeine related deaths
Forensic Science International, 2016Co-Authors: Joachim Frost, Trine N. Løkken, Ivar Skjåk Nordrum, Arne Helland, Lars SlørdalAbstract: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 (0.0080 mg/L and 0.058 mg/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.
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A validated method for simultaneous determination of codeine, codeine-6-glucuronide, Norcodeine, morphine, morphine-3-glucuronide and morphine-6-glucuronide in post-mortem blood, vitreous fluid, muscle, fat and brain tissue by LC-MS.
Journal of Analytical Toxicology, 2015Co-Authors: Joachim Frost, Trine N. Løkken, Wenche Rødseth Brede, Solfrid Hegstad, Ivar Skjåk Nordrum, Lars SlørdalAbstract:The toxicodynamics and, to a lesser degree, toxicokinetics of the widely used opiate codeine remain a matter of controversy. To address this issue, analytical methods capable of providing reliable quantification of codeine metabolites alongside codeine concentrations are required. This article presents a validated method for simultaneous determination of codeine, codeine metabolites codeine-6-glucuronide (C6G), Norcodeine and morphine, and morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem whole blood, vitreous fluid, muscle, fat and brain tissue by high-performance liquid chromatography mass spectrometry. Samples were prepared by solid-phase extraction. The validated ranges were 1.5–300 ng/mL for codeine, Norcodeine and morphine, and 23–4,600 ng/mL for C6G, M3G and M6G, with exceptions for Norcodeine in muscle (3 – 300 ng/mL), morphine in muscle, fat and brain (3–300 ng/mL) and M6G in fat (46–4,600 ng/mL). Within-run and between-run accuracy (88.1–114.1%) and precision (CV 0.6–12.7%), matrix effects (CV 0.3–13.5%) and recovery (57.8–94.1%) were validated at two concentration levels; 3 and 150 ng/mL for codeine, Norcodeine and morphine, and 46 and 2,300 ng/mL for C6G, M3G and M6G. Freeze– thaw and long-term stability (6 months at 28088C) was assessed, showing no significant changes in analyte concentrations (212 to 18%). The method was applied in two authentic forensic autopsy cases implicating codeine in both therapeutic and presumably lethal concentration levels.
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Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths
Forensic Science International, 2012Co-Authors: Joachim Frost, Ivar Skjåk Nordrum, Arne Helland, Lars SlørdalAbstract: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.
Edward J Cone - One of the best experts on this subject based on the ideXlab platform.
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urine testing for Norcodeine norhydrocodone and noroxycodone facilitates interpretation and reduces false negatives
Forensic Science International, 2010Co-Authors: Edward J Cone, Anne Zichterman, Rebecca Heltsley, David L Black, Beverly Cawthon, Tim Robert, Frank Moser, Yale H CaplanAbstract: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 β-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 50 ng/mL. The study was approved by an Institutional Review Board. Of the total specimens ( N = 2654) tested, 71.4% ( N = 1895) were positive (≥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.
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Urine Drug Testing of Chronic Pain Patients. II. Prevalence Patterns of Prescription Opiates and Metabolites
Journal of Analytical Toxicology, 2010Co-Authors: Rebecca Heltsley, Anne Zichterman, David L Black, Beverly Cawthon, Tim Robert, Frank Moser, Yale H Caplan, Edward J ConeAbstract: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.
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Urine testing for Norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives.
Forensic science international, 2009Co-Authors: Edward J Cone, Anne Zichterman, Rebecca Heltsley, David L Black, Beverly Cawthon, Tim Robert, Frank Moser, Yale H CaplanAbstract: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.
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Identification and quantitation of amphetamines, cocaine, opiates, and phencyclidine in oral fluid by liquid chromatography-tandem mass spectrometry.
Journal of Analytical Toxicology, 2009Co-Authors: Dean Fritch, Kristen Blum, Sheena Nonnemacher, Brenda J. Haggerty, Matthew P. Sullivan, Edward J ConeAbstract:Analytical methods for measuring multiple licit and illicit drugs and metabolites in oral fluid require high sensitivity, specificity, and accuracy. With the limited volume available for testing, comprehensive methodology is needed for simultaneous measurement of multiple analytes in a single aliquot.This report describes the validation of a semi-automated method for the simultaneous extraction, identification, and quantitation of 21 analytes in a single oral fluid aliquot.The target compounds included are amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxyethylamphetamine, pseudoephedrine, cocaine, benzoylecgonine, codeine, Norcodeine, 6-acetylcodeine, morphine, 6-acetylmorphine, hydrocodone, norhydrocodone, dihydrocodeine, hydromorphone, oxycodone, noroxycodone, oxymorphone, and phencyclidine. Oral fluid specimens were collected with the Intercept ® device and extracted by solid-phase extraction (SPE). Drug recovery from the Intercept device averaged 84.3%, and SPE extraction efficiency averaged 91.2% for the 21 analytes. Drug analysis was performed by liquid chromatography‐tandem mass spectrometry in the positive electrospray mode using ratios of qualifying product ions within ±25% of calibration standards. Matrix ion suppression ranged from ‐57 to 8%.The limit of quantitation ranged from 0.4 to 5 ng/mL using 0.2 mL of diluted oral fluid sample. Application of the method was demonstrated by testing oral fluid specimens from drug abuse treatment patients.Thirty-nine patients tested positive for various combinations of licit and illicit drugs and metabolites. In conclusion, this validated method is suitable for simultaneous measurement of 21 licit and illicit drugs and metabolites in oral fluid.
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Plasma and Oral Fluid Pharmacokinetics and Pharmacodynamics after Oral Codeine Administration
Clinical Chemistry, 2002Co-Authors: Allan J. Barnes, Edward J Cone, Robert E. Joseph, Jonathan M. Oyler, Raf Schepers, Diana Lafko, Eric T. Moolchan, Marilyn A. HuestisAbstract:Background: The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results. Methods: Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, Norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography–mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined. Results: Mean (SE) peak codeine concentrations were 214.2 ± 27.6 and 474.3 ± 77.0 μg/L in plasma and 638.4 ± 64.4 and 1599.3 ± 241.0 μg/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant (∼4) from 1 to 12 h. The mean half-life ( t 1/2) of codeine was 2.2 ± 0.10 h in plasma and 2.2 ± 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and “high” occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 μg/L cutoff, longer than that of plasma (12–16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 μg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid. Conclusions: The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7–21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.
Joachim Frost - One of the best experts on this subject based on the ideXlab platform.
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post mortem levels and tissue distribution of codeine codeine 6 glucuronide Norcodeine morphine and morphine glucuronides in a series of codeine related deaths
Forensic Science International, 2016Co-Authors: Joachim Frost, Trine N. Løkken, Ivar Skjåk Nordrum, Arne Helland, Lars SlørdalAbstract: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 (0.0080 mg/L and 0.058 mg/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.
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A validated method for simultaneous determination of codeine, codeine-6-glucuronide, Norcodeine, morphine, morphine-3-glucuronide and morphine-6-glucuronide in post-mortem blood, vitreous fluid, muscle, fat and brain tissue by LC-MS.
Journal of Analytical Toxicology, 2015Co-Authors: Joachim Frost, Trine N. Løkken, Wenche Rødseth Brede, Solfrid Hegstad, Ivar Skjåk Nordrum, Lars SlørdalAbstract:The toxicodynamics and, to a lesser degree, toxicokinetics of the widely used opiate codeine remain a matter of controversy. To address this issue, analytical methods capable of providing reliable quantification of codeine metabolites alongside codeine concentrations are required. This article presents a validated method for simultaneous determination of codeine, codeine metabolites codeine-6-glucuronide (C6G), Norcodeine and morphine, and morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem whole blood, vitreous fluid, muscle, fat and brain tissue by high-performance liquid chromatography mass spectrometry. Samples were prepared by solid-phase extraction. The validated ranges were 1.5–300 ng/mL for codeine, Norcodeine and morphine, and 23–4,600 ng/mL for C6G, M3G and M6G, with exceptions for Norcodeine in muscle (3 – 300 ng/mL), morphine in muscle, fat and brain (3–300 ng/mL) and M6G in fat (46–4,600 ng/mL). Within-run and between-run accuracy (88.1–114.1%) and precision (CV 0.6–12.7%), matrix effects (CV 0.3–13.5%) and recovery (57.8–94.1%) were validated at two concentration levels; 3 and 150 ng/mL for codeine, Norcodeine and morphine, and 46 and 2,300 ng/mL for C6G, M3G and M6G. Freeze– thaw and long-term stability (6 months at 28088C) was assessed, showing no significant changes in analyte concentrations (212 to 18%). The method was applied in two authentic forensic autopsy cases implicating codeine in both therapeutic and presumably lethal concentration levels.
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Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths
Forensic Science International, 2012Co-Authors: Joachim Frost, Ivar Skjåk Nordrum, Arne Helland, Lars SlørdalAbstract: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.
Yoseph Caraco - One of the best experts on this subject based on the ideXlab platform.
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Simultaneous determination of codeine and it seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection
Journal of Chromatography B: Biomedical Sciences and Applications, 1998Co-Authors: Huaibing He, Sheila Shay, Yoseph Caraco, Margaret Wood, Alastair J. J. WoodAbstract: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 C 18 cartridges and separated on a reversed-phase C 8 column with a mobile phase consisting of 77% buffer (5 m M sodium phosphate monobasic and 0.70 m M 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.
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Simultaneous determination of codeine and its seven metabolites in plasma and urine by high-performance liquid chromatography with ultraviolet and electrochemical detection.
Journal of chromatography. B Biomedical sciences and applications, 1998Co-Authors: Huaibing He, Yoseph Caraco, Margaret Wood, S D Shay, Alastair J. J. WoodAbstract: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.
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pharmacogenetic determinants of codeine induction by rifampin the impact on codeine s respiratory psychomotor and miotic effects
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Yoseph Caraco, James R Sheller, Alastair J. J. WoodAbstract:Our objective was to examine the effect of rifampin on codeine’s pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of Norcodeine, Norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine’s respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine’s respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced—and hence codeine’s pharmacodynamic effects were attenuated—in EMs of debrisoquin.
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Pharmacogenetic Determinants of Codeine Induction by Rifampin: The Impact on Codeine’s Respiratory, Psychomotor and Miotic Effects
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Yoseph Caraco, James R Sheller, Alastair J. J. WoodAbstract:Our objective was to examine the effect of rifampin on codeine’s pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of Norcodeine, Norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine’s respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine’s respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced—and hence codeine’s pharmacodynamic effects were attenuated—in EMs of debrisoquin.
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Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity.
Drug Metabolism and Disposition, 1996Co-Authors: Yoseph Caraco, Tomonori Tateishi, F. P. Guengerich, Alastair J. J. WoodAbstract:Codeine is metabolized by glucuronidation, by O-demethylation to morphine, and by N-demethylation to Norcodeine. The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome P4502D6 (CYP2D6). The purpose of the present study was to identify the specific P450 enzyme responsible for codeine N-demethylation. Microsomal preparations (250 pmol of P450) obtained from 12 human liver donors were incubated with 20 microM codeine and analyzed for Norcodeine formation. Codeine N-demethylation activity was linearly correlated with nifedipine oxidation activity (r = 0.90, p < 0.001), a marker of CYP3A4, but not with codeine O-demethylation, a marker of CYP2D6. Preincubation with troleandomycin (50 microM), or gestodene (50 microM) inhibitors of CYP3A4, decreased the rate of production of Norcodeine by 60 and 45% compared to control values, respectively. Similarly, ketoconazole (10 microM) and erythromycin (10 microM) inhibited codeine N-demethylation by 75 and 35%, respectively. In contrast, the presence of quinidine, sulfaphenazole, or diethyldithiocarbamate in the incubation mixture had no effect on Norcodeine formation. Preincubation with antibodies raised to CYP3A4 (5 mg lgG/nmol P450) caused 96% inhibition of Norcodeine production, whereas preimmune IgG or antibodies raised to CYP2A6 and CYP2C had no effect. Additionally, significant Norcodeine production was observed with purified CYP3A4 derived from human liver microsomes. In conclusion, codeine N-demethylation activity cosegregates with CYP3A4 activity. Coadministration of codeine with selective inhibitors of CYP3A4 may result in increased morphine production and enhanced pharmacodynamic effects due to shunting down the CYP2D6 pathway.
