Yoshinari Kouichi, Nagai Mika
Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka.
Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd.
Nihon Yakurigaku Zasshi. 2019;153(4):186-191. doi: 10.1254/fpj.153.186.
Drug metabolism in the liver is a major factor affecting pharmacokinetics of drugs, and cytochrome P450s (P450s) are major enzymes responsible for it. Since drug-drug interactions (DDIs) can affect the pharmacokinetics of concomitantly administrated drugs, it may limit the drug therapy such as dose adjustment and contraindications for co-administration and lead to dose adjustment and contraindications for co-administration. DDI is thus one of the risk factors to be reduced in the lead-optimization stage. Therefore, it is important to estimate DDI risk in the early drug discovery stage and develop candidates with low DDI risk. P450 induction is one of the important mechanisms causing DDIs and the activation of nuclear receptors is involved in this phenomenon. In this manuscript, the mechanism and evaluation methods of P450 induction are briefly reviewed, and then the new in silico methods for the prediction of P450 induction, which have been recently established by us, and its application to drug development are introduced.
肝脏中的药物代谢是影响药物药代动力学的主要因素，细胞色素P450（P450）是负责此过程的主要酶。由于药物相互作用（DDIs）会影响同时给药药物的药代动力学，这可能会限制药物治疗，如剂量调整和联合用药的禁忌证，并导致联合用药的剂量调整和禁忌证。因此，DDI是先导优化阶段需要降低的风险因素之一。所以，在药物发现早期阶段评估DDI风险并开发具有低DDI风险的候选药物很重要。P450诱导是导致DDIs的重要机制之一，核受体的激活参与了这一现象。在本手稿中，简要综述了P450诱导的机制和评估方法，然后介绍了我们最近建立的预测P450诱导的新计算机方法及其在药物开发中的应用。
