morphine-6-glucuronide and Substance-Related-Disorders

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.

Topics: Adipose Tissue; Adult; Aged; Brain Chemistry; Chromatography, Liquid; Codeine; Cytochrome P-450 CYP2D6; Female; Forensic Toxicology; Genotype; Humans; Male; Mass Spectrometry; Middle Aged; Morphine; Morphine Derivatives; Muscle, Skeletal; Norway; Postmortem Changes; Solid Phase Extraction; Substance-Related Disorders; Tissue Distribution; Vitreous Body; Young Adult

Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run.. Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards.. The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15%, and the accuracy was between 90 and 115%.. This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important.

Topics: Buprenorphine; Chromatography, Liquid; Forensic Toxicology; Humans; Mass Spectrometry; Methadone; Molecular Structure; Morphine; Morphine Derivatives; Narcotics; Solid Phase Extraction; Stereoisomerism; Substance-Related Disorders

After intake of heroin or morphine, active metabolites are formed in the body. The two most important morphine metabolites are morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G and M3G are present for longer time periods and in higher concentrations than the parent drug, but their potential contribution to reward and to development of dependence and addiction is not clear. We tested the effects of morphine and M6G separately (doses of 10, 20, 30 and 50 micromol/kg), administered together, and also in combination with with 200 microm l/kg M3G in male C57BL/6J-Bom mice. M3G in doses of 50, 100, 200, 300 and 400 micromol/kg were also tested alone. We evaluated the rewarding effects in a conditioning place preference (CPP) model and the psychomotor stimulating effects by recording locomotor activity. Mice were subjected to three consecutive conditioning days with drugs or saline before testing. Changes in locomotor activity from conditioning day one to day three were also compared to the expression of CPP on the test day. This study revealed that coadministration of morphine and M6G induced CPP of similar magnitude to the sum of equimolar doses of these compounds alone, and different ratios of the two drugs did not affect the results. M3G did not cause CPP and reduced the CPP induced by both morphine and M6G when coadministered with these drugs. Morphine induced locomotor activity was reduced by coadministration of M3G, but this was not seen when M3G was co-injected with M6G. The changes in locomotor activity during the conditioning periods did not correlated with the expression of CPP. This study revealed that the morphine-glucuronides in different and complex ways can influence the pharmacological effects of psychomotor activation and reward observed after intake of morphine.

Topics: Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Derivatives; Motor Activity; Reward; Substance-Related Disorders; Time Factors

Topics: Heroin; Heroin Dependence; Humans; Morphine; Morphine Derivatives; Naloxone; Substance-Related Disorders