Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion
Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion
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DOI：
10.1111/j.1365-2125.2009.03519.x
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发表时间：
2009-11-01
影响因子：
3.4
通讯作者：
Court, Michael H.
中科院分区：
文献类型：
--
作者：
He, Xi;Hesse, Leah M.;Court, Michael H.
中心点UDP-葡萄糖醛酸基转移酶（UGT）2B15是一种在人体中表达的主要药物葡萄糖醛酸化酶。奥沙西泮是一种异构体选择性探针药物，用于体外研究。15错义多态性（D85 Y和K523 T）与人肝脏库中可变的奥沙西泮葡萄糖醛酸化相关。UGT 2B17也在肝脏中表达，与UGT 2B15具有高度序列同源性和底物特异性重叠。这项研究补充的是，中心点UGT 2B15 D85 Y多态性被确定为奥沙西泮处置的主要决定因素，占奥沙西泮表观口服给药个体间变异性的34%。3T或UGT2B17缺失多态性对奥沙西泮处置的影响不能是www.example.com dot提供支持使用奥沙西泮作为同种型的证据-liver.center本研究的主要目的是确定UGT2B15基因（D85Y和K523T）中常见的错义多态性是否与奥沙西泮的药代动力学和药效学改变相关。方法30例健康男性受试者口服15 mg奥沙西泮36 h，监测血药浓度，8 h进行药效学试验。用基因组聚合酶链反应和5 ′-核酸酶分析方法进行基因分型，发现D85Y、K523T、UGT 2B17del的等位基因频率分别为47%、23%和19%。与85 DD受试者（3.35 ml min-1 kg-1; P = 0.003，Student-Newman-Keuls检验）相比，85 YY受试者的奥沙西泮表观口服清除率中位数（1.62 ml min-1 kg-1）显着较低，而85 DY受试者居中（2.34 ml min-1 kg-1; P = 0.018 vs. 85 DD，P = 0.034 vs. 85 YY）。回归分析表明，UGT 2B15 D85Y基因型可解释34%的个体间变异。然而，UGT 2B15 K523 T和UGT 2B17 del均与奥沙西泮处置改变无关。此外，没有差异的药效学措施，包括定量脑电图，数字符号替代试验，自我或self-verated视觉模拟量表，可以证明任何的多态性evaluated.CONCLUSIONSThese结果确定UGT2B15 D85Y作为奥沙西泮清除率的主要决定因素，并表明奥沙西泮可能是有用的体内探头葡萄糖醛酸化的UGT2B15。
center dot UDP-glucuronosyltransferase (UGT) 2B15 is a major drug glucuronidation enzyme expressed in human liver.center dot Oxazepam is an isoform-selective probe drug that is being used for in vitro studies of UGT2B15.center dot The most common UGT2B15 missense polymorphisms (D85Y and K523T) are correlated with variable oxazepam glucuronidation in human liver bank samples.center dot UGT2B17 is also expressed in liver and has high sequence homology and substrate specificity overlap with UGT2B15.WHAT THIS STUDY ADDScenter dot 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.center dot An effect of the UGT2B15 K523T or the UGT2B17 deletion polymorphisms on oxazepam disposition could not be detected.center dot Provides evidence supporting the use of oxazepam as an isoform-selective in vivo probe for studies of variability in UGT2B15 activity.AIMSAlthough 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.METHODSThirty 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.RESULTSAllele 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.CONCLUSIONSThese 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.