Interindividual variability in the glucuronidation of (S) oxazepam contrasted with that of (R) oxazepam

Patel, Mitesh; Tang, Boxin; Grant, D M; Kalow, W

doi:10.1097/00008571-199510000-00004

Cited by 49 publications

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“…Furthermore, the effects of gender and D85Y genotype on S/R-oxazepam glucuronidation ratios consistently showed higher p values than effects on S-oxazepam glucuronidation activities. Ratios of S-oxazepam glucuronide to R-oxazepam glucuronide concentrations in urine and blood have also been used to quantify oxazepam metabolism in human subjects (Patel et al, 1995a). In fact, the S/R-oxazepam glucuronide concentration ratio measured in urine collected over the first 8 h after oxazepam administration is an excellent predictor (r s ϭ 0.90) of the plasma clearance of oxazepam (Patel et al, 1995a).…”

Section: Ugt2b15 Pharmacogenetics 661mentioning

confidence: 99%

“…This finding was considered by the investigators to be consistent with the presence of a slow metabolizer phenotype in the population. Further in vitro studies (Patel et al, 1995a) with human liver microsomes (HLMs) verified S-oxazepam glucuronide as the major metabolite (S/R ratios averaging 4.0) and also identified 4 of 37 (11%) livers with relatively low oxazepam glucuronidation activities (S/R metabolite ratios Ͻ2.0). Enzyme kinetic analysis of S-oxazepam glucuronidation suggested that these low activities were associated with higher K m values and lower V max values for the four atypical livers compared with the remaining livers.…”

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confidence: 95%

“…Oxazepam, a commonly used 1,4-benzodiazepine anxiolytic drug, is of considerable interest because it is cleared primarily by glucuronidation and has been used extensively as an in vivo probe of drug glucuronidation in people (Greenblatt et al, 1980(Greenblatt et al, , 1984Greenblatt, 1981;Sonne, 1993). Furthermore, the glucuronidation of this drug by human subjects is known to be polymorphic (Patel et al, 1995a), although the molecular mechanisms responsible for this variability are not well understood.…”

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confidence: 99%

“…A previous study of oxazepam biotransformation in human subjects by Patel et al (1995a) identified S-oxazepam glucuronide as the major oxazepam metabolite in human plasma This work was supported by Grants GM-61834, DA-05258, MH-58435, DA-13209, DK-58496, AG-17880, AT-01381, and RR-00054 from the National Institutes of Health.…”

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confidence: 99%

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UDP-Glucuronosyltransferase (UGT) 2B15 Pharmacogenetics: UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver

Court

Qin

Krishnaswamy

et al. 2004

J Pharmacol Exp Ther

102

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Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. However, the molecular basis for this phenomenon is currently unknown. We have previously shown that S-oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by UDPglucuronosyltransferase (UGT) 2B15, whereas the minor Roxazepam glucuronide is produced by multiple UGTs other than UGT2B15. Phenotype-genotype studies were conducted using microsomes and DNA prepared from the same set of 54 human livers. Sequencing of the UGT2B15 gene revealed three nonsynonymous polymorphisms, D85Y, T352I, and K523T, with variant allele frequencies of 0.56, 0.02, and 0.40, respectively. D85Y genotype showed a significant effect (p ϭ 0.012) on S-oxazepam glucuronidation with lower median activities in 85Y/Y livers (49 pmol/min/mg protein) compared with 85D/D livers (131 pmol/min/mg), whereas 85D/Y livers were intermediate in activity (65 pmol/min/mg). There was also a significant trend (p ϭ 0.049) for higher S-oxazepam activities in the two 352T/I livers (135 and 210 pmol/min/mg) compared with the remaining 352T/T livers (median, 64 pmol/min/mg). Conversely, K523T genotype had no apparent effect on oxazepam glucuronidation (p Ͼ 0.05). Donor gender also significantly influenced S-oxazepam glucuronidation with higher median activities in male (65 pmol/min/mg) compared with female (39 pmol/min/ mg) livers (p ϭ 0.042). R-Oxazepam glucuronidation was not affected by either genotype or gender (p Ͼ 0.05). In conclusion, gender and D85Y genotype are identified as major determinants of S-oxazepam glucuronidation by human liver and may explain in part polymorphic oxazepam glucuronidation by human subjects.Glucuronidation, catalyzed by the UDP-glucuronosyltransferases (UGTs), is one of the major metabolic pathways responsible for elimination of potentially harmful xenobiotic and endobiotic compounds in mammals. UGT2B15 is one of more than 16 human UGT isoforms that have been discovered to date. Although originally identified as an enzyme with high intrinsic activity for glucuronidation of androgenic steroids (Chen et al., 1993), subsequent studies with recombinant UGT2B15 indicate that this enzyme is also likely to have a significant role in the metabolism of drugs and other xenobiotics (Green et al., 1994).

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Section: Ugt2b15 Pharmacogenetics 661mentioning

confidence: 99%

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confidence: 95%

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confidence: 99%

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UDP-Glucuronosyltransferase (UGT) 2B15 Pharmacogenetics: UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver

Court

Qin

Krishnaswamy

et al. 2004

J Pharmacol Exp Ther

102

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“…Recently, oxazepam administered as a racemic mixture was shown to be preferentially excreted as the (S)-glucuronide and a low SIR glucuronide ratio was used to assess poor glucuronidation of oxazepam (29). A group of 10% of the whole population was determined to be poor glucuronidators of (S)-oxazepam which suggested a genetic relationship to the UGT2B7 isoform.…”

Section: Known Polymorphisms Of Glucuronidation In Manmentioning

confidence: 99%

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Burchell

Coughtrie

1997

Environ Health Perspect

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Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. Environ Health Perspect 1 05(Suppl 4): 739-747 (1997)

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Pharmacogenetics and Ethnoracial Differences in Smoking

Sellers¹

1998

JAMA

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Interindividual variability in the glucuronidation of (S) oxazepam contrasted with that of (R) oxazepam

Cited by 49 publications

References 0 publications

UDP-Glucuronosyltransferase (UGT) 2B15 Pharmacogenetics: UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver

UDP-Glucuronosyltransferase (UGT) 2B15 Pharmacogenetics: UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Pharmacogenetics and Ethnoracial Differences in Smoking

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