Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/17673
Citations
Scopus Web of Science® Altmetric
?
?
Full metadata record
DC FieldValueLanguage
dc.contributor.authorMorrish, G.-
dc.contributor.authorFoster, D.-
dc.contributor.authorSomogyi, A.-
dc.date.issued2006-
dc.identifier.citationBritish Journal of Clinical Pharmacology, 2006; 61(3):326-335-
dc.identifier.issn0306-5251-
dc.identifier.issn1365-2125-
dc.identifier.urihttp://hdl.handle.net/2440/17673-
dc.descriptionThe definitive version is available at www.blackwell-synergy.com-
dc.description.abstractAIMS: To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. METHODS: M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70–500 µm) using three microsomal samples. RESULTS: Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean ± SD) was 4.8-fold greater than M6G Vmax (555 ± 110 vs. 115 ± 19 nmol mg1 protein h1; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg1 protein h1). Km values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 mm; P = 0.89, 0.02; − 0.29, 0.32 mm). M3G and M6G formation was inhibited (P < 0.01) with a significant increase in the M3G/M6G ratio (P < 0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320 ± 42 µm and 192 ± 12 µm for M3G and M6G, respectively, and (S)-methadone Ki of 226 ± 30 µm and 152 ± 20 µm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P = 0.017, 128; 55, 202 µm) and (S)-methadone (P = 0.026, 75; 22, 128 µm). CONCLUSIONS: Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G.-
dc.description.statementofresponsibilityGlynn A. Morrish, David J. R. Foster and Andrew A. Somogyi-
dc.language.isoen-
dc.publisherBlackwell Publishing Ltd-
dc.source.urihttp://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2005.02573.x-
dc.subjectMicrosomes, Liver-
dc.subjectHumans-
dc.subjectMethadone-
dc.subjectMethadyl Acetate-
dc.subjectMorphine Derivatives-
dc.subjectAlamethicin-
dc.subjectAnalgesics, Opioid-
dc.subjectIonophores-
dc.subjectDextropropoxyphene-
dc.titleDifferential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids-
dc.typeJournal article-
dc.identifier.doi10.1111/j.1365-2125.2005.02573.x-
pubs.publication-statusPublished-
dc.identifier.orcidFoster, D. [0000-0002-7345-4084]-
dc.identifier.orcidSomogyi, A. [0000-0003-4779-0380]-
Appears in Collections:Aurora harvest 6
Pharmacology publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.