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David J Greenblatt - One of the best experts on this subject based on the ideXlab platform.
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Evidence for Oxazepam as an in vivo probe of UGT2B15: Oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion
British journal of clinical pharmacology, 2009Co-Authors: Leah M. Hesse, David J Greenblatt, Jerold S Harmatz, Suwagmani Hazarika, Gina Masse, Michael H CourtAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • UDP-glucuronosyltransferase (UGT) 2B15 is a major drug glucuronidation enzyme expressed in human liver. • Oxazepam is an isoform-selective probe drug that is being used for in vitro studies of UGT2B15. • The most common UGT2B15 missense polymorphisms (D85Y and K523T) are correlated with variable Oxazepam glucuronidation in human liver bank samples. • UGT2B17 is also expressed in liver and has high sequence homology and substrate specificity overlap with UGT2B15. WHAT THIS STUDY ADDS • UGT2B15 D85Y polymorphism is identified as a major determinant of Oxazepam disposition, accounting for as much as 34% of interindividual variability in Oxazepam apparent oral clearance. • An effect of the UGT2B15 K523T or the UGT2B17 deletion polymorphisms on Oxazepam disposition could not be detected. • Provides evidence supporting the use of Oxazepam as an isoform-selective in vivo probe for studies of variability in UGT2B15 activity. AIMS Although in vitro studies indicate that Oxazepam is an isoform-selective substrate probe for UDP-glucuronosyltransferase 2B15, the utility of this drug as an in vivo probe is uncertain. The main aim of this study was to determine whether common missense polymorphisms in the UGT2B15 gene (D85Y and K523T) are associated with altered Oxazepam pharmacokinetics and pharmacodynamics. We also determined the possible influence of a common deletion polymorphism in the gene encoding UGT2B17, which shows substantial substrate specificity overlap with UGT2B15. METHODS Thirty healthy male subjects were administered 15 mg of Oxazepam by mouth followed by plasma Oxazepam concentration monitoring for 36 h, and pharmacodynamic testing for 8 h. Genotypes were determined by genomic polymerase chain reaction and commercial 5′-nuclease assays. RESULTS Allele frequencies for D85Y, K523T, UGT2B17del were 47%, 23% and 19%, respectively. Median Oxazepam apparent oral clearance was significantly lower in 85YY subjects (1.62 ml min−1 kg−1) compared with 85DD subjects (3.35 ml min−1 kg−1; P= 0.003, Student–Newman–Keuls test), whereas 85DY subjects were intermediate (2.34 ml min−1 kg−1; P= 0.018 vs. 85DD, P= 0.034 vs. 85YY). Regression analysis indicated that UGT2B15 D85Y genotype accounted for 34% of interindividual variability. However, neither UGT2B15 K523T nor UGT2B17del was associated with altered Oxazepam disposition. Furthermore, no differences in pharmacodynamic measures, including quantitative electroencephalography, digit-symbol substitution test, self- or observer-rated visual analogue scales, could be demonstrated for any of the polymorphisms evaluated. CONCLUSIONS These results identify UGT2B15 D85Y as a major determinant of Oxazepam clearance, and indicate that Oxazepam may be useful as an in vivo probe for glucuronidation by UGT2B15.
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udp glucuronosyltransferase ugt 2b15 pharmacogenetics ugt2b15 d85y genotype and gender are major determinants of Oxazepam glucuronidation by human liver
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Michael H Court, Soundararajan Krishnaswamy, Qin Hao, Tanios Bekaiisaab, Abdul Alrohaimi, Lisa L Von Moltke, David J GreenblattAbstract: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 UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor R Oxazepam 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 = 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 = 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 > 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 = 0.042). R -Oxazepam glucuronidation was not affected by either genotype or gender ( p > 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.
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stereoselective conjugation of Oxazepam by human udp glucuronosyltransferases ugts s Oxazepam is glucuronidated by ugt2b15 while r Oxazepam is glucuronidated by ugt2b7 and ugt1a9
Drug Metabolism and Disposition, 2002Co-Authors: Michael H Court, Su X Duan, Chantal Guillemette, Kim Journault, Soundararajan Krishnaswamy, Lisa L Von Moltke, David J GreenblattAbstract:(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-Oxazepam (but not R-Oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-Oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-Oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-Oxazepam glucuronidation. Furthermore, the apparent Km for UGT2B15 (29–35 μM) was similar to values determined for HLMs (43–60 μM). In contrast, R-Oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent Km values for HLMs (256–303 μM) were most similar to UGT2B7 (333 μM) rather than UGT1A9 (12 μM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higherS-Oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3α-diol. In conclusion, S-Oxazepam is stereoselectively glucuronidated by UGT2B15, whereasR-Oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-Oxazepam glucuronidation in humans.
Michael H Court - One of the best experts on this subject based on the ideXlab platform.
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Evidence for Oxazepam as an in vivo probe of UGT2B15: Oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion
British journal of clinical pharmacology, 2009Co-Authors: Leah M. Hesse, David J Greenblatt, Jerold S Harmatz, Suwagmani Hazarika, Gina Masse, Michael H CourtAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • UDP-glucuronosyltransferase (UGT) 2B15 is a major drug glucuronidation enzyme expressed in human liver. • Oxazepam is an isoform-selective probe drug that is being used for in vitro studies of UGT2B15. • The most common UGT2B15 missense polymorphisms (D85Y and K523T) are correlated with variable Oxazepam glucuronidation in human liver bank samples. • UGT2B17 is also expressed in liver and has high sequence homology and substrate specificity overlap with UGT2B15. WHAT THIS STUDY ADDS • UGT2B15 D85Y polymorphism is identified as a major determinant of Oxazepam disposition, accounting for as much as 34% of interindividual variability in Oxazepam apparent oral clearance. • An effect of the UGT2B15 K523T or the UGT2B17 deletion polymorphisms on Oxazepam disposition could not be detected. • Provides evidence supporting the use of Oxazepam as an isoform-selective in vivo probe for studies of variability in UGT2B15 activity. AIMS Although in vitro studies indicate that Oxazepam is an isoform-selective substrate probe for UDP-glucuronosyltransferase 2B15, the utility of this drug as an in vivo probe is uncertain. The main aim of this study was to determine whether common missense polymorphisms in the UGT2B15 gene (D85Y and K523T) are associated with altered Oxazepam pharmacokinetics and pharmacodynamics. We also determined the possible influence of a common deletion polymorphism in the gene encoding UGT2B17, which shows substantial substrate specificity overlap with UGT2B15. METHODS Thirty healthy male subjects were administered 15 mg of Oxazepam by mouth followed by plasma Oxazepam concentration monitoring for 36 h, and pharmacodynamic testing for 8 h. Genotypes were determined by genomic polymerase chain reaction and commercial 5′-nuclease assays. RESULTS Allele frequencies for D85Y, K523T, UGT2B17del were 47%, 23% and 19%, respectively. Median Oxazepam apparent oral clearance was significantly lower in 85YY subjects (1.62 ml min−1 kg−1) compared with 85DD subjects (3.35 ml min−1 kg−1; P= 0.003, Student–Newman–Keuls test), whereas 85DY subjects were intermediate (2.34 ml min−1 kg−1; P= 0.018 vs. 85DD, P= 0.034 vs. 85YY). Regression analysis indicated that UGT2B15 D85Y genotype accounted for 34% of interindividual variability. However, neither UGT2B15 K523T nor UGT2B17del was associated with altered Oxazepam disposition. Furthermore, no differences in pharmacodynamic measures, including quantitative electroencephalography, digit-symbol substitution test, self- or observer-rated visual analogue scales, could be demonstrated for any of the polymorphisms evaluated. CONCLUSIONS These results identify UGT2B15 D85Y as a major determinant of Oxazepam clearance, and indicate that Oxazepam may be useful as an in vivo probe for glucuronidation by UGT2B15.
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udp glucuronosyltransferase ugt 2b15 pharmacogenetics ugt2b15 d85y genotype and gender are major determinants of Oxazepam glucuronidation by human liver
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Michael H Court, Soundararajan Krishnaswamy, Qin Hao, Tanios Bekaiisaab, Abdul Alrohaimi, Lisa L Von Moltke, David J GreenblattAbstract: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 UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor R Oxazepam 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 = 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 = 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 > 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 = 0.042). R -Oxazepam glucuronidation was not affected by either genotype or gender ( p > 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.
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stereoselective conjugation of Oxazepam by human udp glucuronosyltransferases ugts s Oxazepam is glucuronidated by ugt2b15 while r Oxazepam is glucuronidated by ugt2b7 and ugt1a9
Drug Metabolism and Disposition, 2002Co-Authors: Michael H Court, Su X Duan, Chantal Guillemette, Kim Journault, Soundararajan Krishnaswamy, Lisa L Von Moltke, David J GreenblattAbstract:(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-Oxazepam (but not R-Oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-Oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-Oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-Oxazepam glucuronidation. Furthermore, the apparent Km for UGT2B15 (29–35 μM) was similar to values determined for HLMs (43–60 μM). In contrast, R-Oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent Km values for HLMs (256–303 μM) were most similar to UGT2B7 (333 μM) rather than UGT1A9 (12 μM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higherS-Oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3α-diol. In conclusion, S-Oxazepam is stereoselectively glucuronidated by UGT2B15, whereasR-Oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-Oxazepam glucuronidation in humans.
Michael D. Teehan - One of the best experts on this subject based on the ideXlab platform.
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an examination of differences in the time course of Oxazepam s effects on implicit vs explicit memory
Journal of Psychopharmacology, 1998Co-Authors: Susan E Buffettjerrott, Sally Bird, Sherry H. Stewart, Michael D. TeehanAbstract:The present study was designed to examine the effects of Oxazepam on implicit vs explicit memory processes, as a function of this drug's time course. The effects of Oxazepam (30 mg) or placebo on directly comparable tests of implicit memory (word stem completion) and explicit memory (cued recall) were examined at three time points: 100 min post-drug administration (prior to the theoretical peak plasma concentration of Oxazepam; i.e.'pre-peak' condition), 170 min post-drug (close to theoretical peak; i.e. 'peak' condition) or 240 min post-drug (following theoretical peak: i.e. 'post-peak' condition). Sixty healthy volunteers were randomly assigned to either the drug condition or the placebo condition in a double-blind design and were tested on both memory tests at one of the three time points. In the 'pre-peak' condition, Oxazepam impaired cued recall performance relative to placebo but did not impair priming. In the 'peak' condition, Oxazepam impaired performance on both memory tasks. In the 'post-peak' condition, cued recall performance in the Oxazepam group remained significantly impaired relative to placebo. However, Oxazepam-induced impairments in priming were only marginal, suggesting that Oxazepam-induced impairments in implicit memory processes begin to wane following theoretical peak drug concentrations. The fact that Oxazepam-induced priming impairments were significant only when the word stem completion task was administered close to peak plasma concentrations, supports the hypothesis that benzodiazepines exert time-dependent effects on implicit memory processes. The results also support the theoretical distinction between implicit and explicit memory processes, since the directly comparable implicit and explicit tasks showed different impairment curves over time.
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An examination of differences in the time course of Oxazepam's effects on implicit vs explicit memory
Journal of Psychopharmacology, 1998Co-Authors: Susan Elizabeth. Buffett-jerrott, Sally Bird, Sherry H. Stewart, Michael D. TeehanAbstract:The present study was designed to examine the effects of Oxazepam on implicit vs explicit memory processes, as a function of this drug's time course. The effects of Oxazepam (30 mg) or placebo on directly comparable tests of implicit memory (word stem completion) and explicit memory (cued recall) were examined at three time points: 100 min post-drug administration (prior to the theoretical peak plasma concentration of Oxazepam; i.e. 'pre- peak' condition), 170 min post-drug (close to theoretical peak; i.e. 'peak' condition) or 240 min post-drug (following theoretical peak: i.e. 'post-peak' condition). Sixty healthy volunteers were randomly assigned to either the drug condition or the placebo condition in a double-blind design and were tested on both memory tests at one of the three time points. In the 'pre-peak' condition, Oxazepam impaired cued recall performance relative to placebo but did not impair priming. In the 'peak' condition, Oxazepam impaired performance on both memory tasks. In the 'post-peak'...
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effects of Oxazepam and lorazepam on implicit and explicit memory evidence for possible influences of time course
Psychopharmacology, 1996Co-Authors: Sherry H. Stewart, George F Rioux, John F Connolly, Sandra C Dunphy, Michael D. TeehanAbstract:The effects of Oxazepam (30 mg), lorazepam (2 mg), and placebo on implicit and explicit memory were studied in two testing cycles, 100 and 170 min after drug administration. Thirty healthy volunteers were randomly assigned to one of three groups (placebo, Oxazepam, or lorazepam) in a double-blind, independent groups design. Drug groups were equivalent prior to drug administration on a variety of cognitive measures. Following drug administration, both Oxazepam and lorazepam equally impaired performance on a cued-recall explicit memory task relative to placebo, at both testing cycles. Relative to placebo, lorazepam markedly impaired priming on a word-stem completion implicit memory task, at both testing cycles. Consistent with previous work, Oxazepam failed to produce impairments in priming on the word-stem completion task at 100 min post-drug administration. However, Oxazepam was found significantly to impair priming on this latter task relative to placebo, at close to theoretical peak plasma concentration (i.e., 170 min post-drug administration). Explanations for the observed detrimental effect of Oxazepam on implicit memory task performance are considered, including: possible time-dependent effects related to the relative rate of absorption of these two benzodiazepines (BZs); and potential contamination of the implicit memory task by explicit memory strategies during the second testing cycle.
Soundararajan Krishnaswamy - One of the best experts on this subject based on the ideXlab platform.
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udp glucuronosyltransferase ugt 2b15 pharmacogenetics ugt2b15 d85y genotype and gender are major determinants of Oxazepam glucuronidation by human liver
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Michael H Court, Soundararajan Krishnaswamy, Qin Hao, Tanios Bekaiisaab, Abdul Alrohaimi, Lisa L Von Moltke, David J GreenblattAbstract: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 UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor R Oxazepam 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 = 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 = 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 > 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 = 0.042). R -Oxazepam glucuronidation was not affected by either genotype or gender ( p > 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.
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stereoselective conjugation of Oxazepam by human udp glucuronosyltransferases ugts s Oxazepam is glucuronidated by ugt2b15 while r Oxazepam is glucuronidated by ugt2b7 and ugt1a9
Drug Metabolism and Disposition, 2002Co-Authors: Michael H Court, Su X Duan, Chantal Guillemette, Kim Journault, Soundararajan Krishnaswamy, Lisa L Von Moltke, David J GreenblattAbstract:(R,S)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that is metabolized primarily by hepatic glucuronidation. In previous studies, S-Oxazepam (but not R-Oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study was to identify UDP-glucuronosyltransferase (UGT) isoforms mediating R- and S-Oxazepam glucuronidation in human liver, with the long term objective of elucidating the molecular genetic basis for this drug metabolism polymorphism. All available recombinant UGT isoforms were screened for R- and S-Oxazepam glucuronidation activities. Enzyme kinetic parameters were then determined in representative human liver microsomes (HLMs) and in UGTs that showed significant activity. Of 12 different UGTs evaluated, only UGT2B15 showed significant S-Oxazepam glucuronidation. Furthermore, the apparent Km for UGT2B15 (29–35 μM) was similar to values determined for HLMs (43–60 μM). In contrast, R-Oxazepam was glucuronidated by UGT1A9 and UGT2B7. Although apparent Km values for HLMs (256–303 μM) were most similar to UGT2B7 (333 μM) rather than UGT1A9 (12 μM), intrinsic clearance values for UGT1A9 were 10 times higher than for UGT2B7. A common genetic variation results in aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 of the UGT2B15 protein. Microsomes from human embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 showed 5 times higherS-Oxazepam glucuronidation activity than did UGT2B15*2 microsomes. Similar results were obtained for other substrates, including eugenol, naringenin, 4-methylumbelliferone, and androstane-3α-diol. In conclusion, S-Oxazepam is stereoselectively glucuronidated by UGT2B15, whereasR-Oxazepam is glucuronidated by multiple UGT isoforms. Allelic variation associated with the UGT2B15 gene may explain polymorphic S-Oxazepam glucuronidation in humans.
Elisabeth Leere Oiestad - One of the best experts on this subject based on the ideXlab platform.
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detection time of Oxazepam and zopiclone in urine and oral fluid after experimental oral dosing
Journal of Analytical Toxicology, 2019Co-Authors: Lina Dorthea Bruun, Kari Kjeldstadli, Vidar Temte, Morris Birdal, Liliana Bachs, Marit Langodegard, Dag Helge Strand, Kristin Irene Gaare, Elisabeth Leere OiestadAbstract:Data from previous experimental studies on the detection time of Oxazepam and zopiclone in biological matrices are limited. The aim of this study was to examine the detection time in urine and oral fluid after single oral doses of Oxazepam and zopiclone. Ten healthy volunteers received 25 mg of Oxazepam in the evening of Day 1 and 7.5 mg of zopiclone in the evening of Day 3. Urine and oral fluid samples were collected twice daily for 9 days, with an additional sampling the day after ingestion of zopiclone. A total of 19 samples of both urine and oral fluid from each participant were analyzed using fully validated chromatographic methods. The median detection time for Oxazepam was 91 h (range 73-108) in urine and 67 h (range 50-98) in oral fluid. The median detection time for zopiclone in urine was 49 h (range 25-98) and 59 h (range 48-146) in oral fluid. The metabolite zopiclone N-oxide showed a detection time of 36 h (range 25-84) in urine. The area under the concentration-time curve (AUCTotal) in urine corrected for creatinine was 150 μmol/L/mmol/L*h (range 105-216) for Oxazepam and 1.60 μmol/L/mmol/L*h (range 0.79-4.53) for zopiclone. In oral fluid, the AUCtotal was 673 nmol/L*h (range 339-1,316) for Oxazepam and 2,150 nmol/L*h (range 493-4,240) for zopiclone. In conclusion, Oxazepam can be detected longer in urine than in oral fluid, while zopiclone can be detected longer in oral fluid than in urine. The high AUCTotal for zopiclone in oral fluid shows that the transfer into oral fluid is significant. In certain individuals the detection time of zopiclone in oral fluid is long. These results can be helpful when interpreting drug testing analyzes.
