Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, 3508 TD, Utrecht, The Netherlands.
Risk Assessment Department, French Agency for Food, Environmental and Occupational Health and Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort, France.
Arch Toxicol. 2020 Aug;94(8):2637-2661. doi: 10.1007/s00204-020-02765-8. Epub 2020 May 15.
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.
UDP-葡糖醛酸基转移酶（UGTs）参与外源性物质的 II 相共轭反应，其同工酶活性的差异导致 UGT 探针底物的个体间动力学差异。在这里，进行了广泛的文献检索，以确定各种 UGT 同工酶（UGT1A1、UGT1A3、UGT1A4、UGT1A6、UGT1A9、UGT2B7 和 UGT2B15）的探针底物（14）及其人类多态性的频率。在数据库中收集了针对特定化学物质的药代动力学数据，以量化急性（Cmax）和慢性（曲线下面积、清除率）暴露标志物的个体间差异。使用该数据库，推导了与 UGT 相关的不确定因素，并将其与默认因素（即 3.16）进行了比较，以考虑动力学方面的个体间差异。总体而言，结果表明药代动力学数据主要可用于白种人群，而其他不同地理来源人群的数据则很少。此外，纳入的研究中很少涉及 UGT 多态性与药代动力学参数之间的关系。数据表明，与 UGT 相关的不确定因素大多低于默认的毒代动力学不确定因素 3.16，除了 5 种探针底物（1-OH-咪达唑仑、依折麦布、雷特格韦、SN38 和三氟拉嗪），其中 3 种底物由多态性同工酶 1A1 代谢。讨论了数据差距和未来的工作，以将与 UGT 相关的变异性分布与体外数据相结合，以开发化学风险评估中的定量体外-体内外推法。
