Drug Metabolism and Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Drug Metab Rev. 2011 Nov;43(4):476-98. doi: 10.3109/03602532.2011.597401. Epub 2011 Aug 23.
Intestinal first-pass metabolism has a great impact on the bioavailability of cytochrome P450 3A4 (CYP3A) and/or uridine 5'-diphosphate (UDP)-glucoronosyltranferase (UGT) substrates in humans. In vitro and in vivo intestinal metabolism studies are essential for clarifying pharmacokinetics in animal species and for predicting the effects of human intestinal metabolism. We review species differences in intestinal metabolism both in vitro and in vivo. Based on mRNA expression levels, the major intestinal CYP3A isoform is CYP3A4 for humans, CYP3A4 (3A8) for monkeys, CYP3A9 for rats, cyp3a13 for mice, and CYP3A12 for dogs. Additionally, the intestinal-specific UGT would be UGT1A10 for humans, UGT1A8 for monkeys, and UGT1A7 for rats. In vitro and in vivo intestinal metabolism of CYP3A substrates were larger in monkeys than in humans, although a correlation in intestinal availability between monkeys and humans has been reported. Little information is available regarding species differences in in vitro and in vivo UGT activities; however, UGT-mediated in vivo intestinal metabolism has been demonstrated for raloxifene in humans and for baicalein in rats. Further assessment of intestinal metabolism, particularly for UGT substrates, is required to clarify the entire picture of species differences.
肠首过代谢对细胞色素 P450 3A4（CYP3A）和/或尿苷 5'-二磷酸（UDP）-葡糖醛酸基转移酶（UGT）在人类中的生物利用度有很大影响。体外和体内肠代谢研究对于阐明动物物种中的药代动力学和预测人类肠道代谢的影响至关重要。我们综述了体内和体外肠道代谢的种属差异。基于 mRNA 表达水平，人类主要的肠道 CYP3A 同工酶为 CYP3A4，猴子为 CYP3A4（3A8），大鼠为 CYP3A9，小鼠为 cyp3a13，狗为 CYP3A12。此外，肠道特异性 UGT 为人类的 UGT1A10，猴子的 UGT1A8 和大鼠的 UGT1A7。尽管已经报道了猴子和人类之间肠道可用性的相关性，但 CYP3A 底物的体外和体内肠代谢在猴子中比在人类中更大。关于体外和体内 UGT 活性的种属差异的信息很少，但已经证明了在人类中 raloxifene 和在大鼠中 baicalein 的 UGT 介导的体内肠代谢。需要进一步评估肠道代谢，特别是 UGT 底物，以阐明种属差异的全貌。
