Miners John O, Smith Paul A, Sorich Michael J, McKinnon Ross A, Mackenzie Peter I
Department of Clinical Pharmacology, Flinders University and Flinders Medical Center, Bedford Park, Adelaide, SA 5042, Australia.
Annu Rev Pharmacol Toxicol. 2004;44:1-25. doi: 10.1146/annurev.pharmtox.44.101802.121546.
Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which both exist as enzyme "superfamilies," are together responsible for the metabolism of most hepatically cleared drugs. There is currently intense interest in the development of techniques that permit identification of the CYP and UGT isoform(s) involved in the metabolism of a newly discovered drug, and hence prediction of factors likely to alter elimination in vivo. In addition, the quantitative scaling of kinetic parameters for a metabolic pathway assumes importance for identifying newly discovered drugs with undesirable in vivo pharmacokinetic properties. Although qualitative and quantitative in vitro-in vivo correlation based on data generated using human liver tissue or recombinant enzymes have been applied successfully to many drugs eliminated by CYP, these strategies have proved less definitive for glucuronidated compounds. Computational (in silico) modeling techniques that potentially provide a facile and economic alternative to the in vitro methods are now emerging. This review assesses the utility of in vitro and in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters and the challenges facing the development of generalizable models.
细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）均以酶“超家族”形式存在，它们共同负责大多数经肝脏清除药物的代谢。目前，人们对开发能够鉴定参与新发现药物代谢的CYP和UGT同工型、从而预测可能改变体内消除的因素的技术有着浓厚兴趣。此外，代谢途径动力学参数的定量标度对于识别具有不良体内药代动力学特性的新发现药物具有重要意义。尽管基于使用人肝组织或重组酶生成的数据的定性和定量体外-体内相关性已成功应用于许多经CYP消除的药物，但这些策略对葡萄糖醛酸化化合物的确定性较低。现在正在出现潜在地为体外方法提供简便且经济替代方案的计算（计算机模拟）建模技术。本综述评估了体外和计算机模拟方法在定性和定量预测药物葡萄糖醛酸化参数方面的效用以及开发通用模型所面临的挑战。
