UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro-in vivo extrapolations in chemical risk assessment are discussed.

中文翻译：

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异构体特异性 UDP-葡萄糖醛酸基转移酶的人类变异性：急性和慢性暴露的标记、多态性和不确定性因素。


UDP-葡萄糖醛酸基转移酶 (UGT) 参与异生素的 II 相缀合反应，其异构体活性的差异导致 UGT 探针底物的个体间动力学差异。在这里，进行了大量的文献检索，以确定各种 UGT 同工型（UGT1A1、UGT1A3、UGT1A4、UGT1A6、UGT1A9、UGT2B7 和 UGT2B15）的探针底物 (14) 和人类多态性的频率。将特定化学品的药代动力学数据收集到数据库中，以量化急性（Cmax）和慢性（曲线下面积、清除率）暴露标记物的个体间差异。使用该数据库，导出与 UGT 相关的不确定性因子，并将其与默认因子（即 3.16）进行比较，以考虑个体间动力学差异。总体而言，结果表明药代动力学数据主要适用于白人人群，而不同地理血统的其他人群则很少。此外，纳入的研究很少讨论 UGT 多态性和药代动力学参数之间的关系。数据显示，除 5 种探针底物（1-OH-咪达唑仑、依折麦布、拉替拉韦、SN38 和三氟拉嗪）​​外，UGT 相关不确定性因子大多低于默认毒代动力学不确定性因子 3.16，其中 3 种底物被代谢由多态异构体 1A1 引起。讨论了数据差距和未来将 UGT 相关变异性分布与体外数据相结合的工作，以开发化学品风险评估中的定量体外-体内外推法。