Polymorphism of drug-metabolyzing enzymes and the assessment of drug efficacy and safety

本课题建立了一种简便可靠的CYP 2C 19基因多态性缺陷的检测方法。在这十年中，CYP 2C 19缺乏症已通过使用探针药物美芬妥英确定，美芬妥英未在日本获得批准。S-美芬妥英是CYP 2C 19最特异的底物，然而，使用美芬妥英测定CYP 2C 19存在许多伦理问题。考虑到这些原因，已将作为CYP 2C 19底物的奥美拉唑用作探针药物。另一方面，三甲双酮已被用于人体内药物代谢酶能力的测定。该化合物在大鼠中通过CYP 2 E1、CYP 2C和CYP 3A亚家族代谢。然而，目前尚不清楚哪种CYP负责三甲双酮代谢。为了阐明三甲双酮和奥美拉唑将作为CYP 2C 19表型分析的探针药物，本研究使用 ...更多信息 38名健康的人类受试者。通过几个时间段后的血液样品来估计药物代谢能力。在38例健康受试者中，奥美拉唑代谢活性呈双峰分布，6例健康受试者的血液中奥美拉唑浓度明显升高，并观察到AUC增加。这6例受试者被区分为CYP 2C 19缺乏症受试者。弱代谢者的频率与先前报告的相似。在这些受试者中，三甲双酮代谢能力呈单峰分布。此外，还使用几种选择性CYP抑制剂在人肝微粒体中进行了曲美双酮代谢。在此条件下，三甲双酮代谢被CYP 2 E1底物氯唑沙宗和CYP 3A 4抑制剂氟康唑强效抑制。这些结果表明，曲美双酮代谢主要由CYP 2 E1介导，而由CYP 3A 4轻微介导。这些结果表明，奥美拉唑将能够通过在口服给药后2和/或3小时采集血样用于CYP 2C 19表型分析。另一方面，三甲双酮将成为体内检测人CYP 2 E1活性的探针药物之一。少

In this project, we have established the simple and reliable procedure for the estimation of genetical polymorphic deficiency of CYP2C19. In this decade, CYP2C19 deficiency had been determined by employing the probe drug, mephenytoin, which is not approved in Japan. S-mephenytoin is the most specific substrate to the CYP2C19, however, employment of mephenytoin for the determination of CYP2C19 has a lot of ethical problems. Taking these reasons into consideration, omeprazole which is the substrate of CYP2C19 has been employed as the probe drug. On the other hand, trimethadione which had been employed for the determination of drug-metobolyzing enzyme capacity in human in vivo. This compound is metabolyzed by CYP2E1, CYP2C and CYP3A subfamilies in rat. However, it is not clear at hand which species of CYPs are responsible for the trimethadione metabolism. To clarify that trimethadione and omeprazole will be the probe drugs for the phenotyping of CYP2C19 this study had performed using the … More 38 healthy human subjects. Drug metabolic capacity was estimated by the blood samples after several time periods. In 38 healthy human subjects, omeprazole metabolic activities were distributed bimodally and 6 of the healthy subjects had the distinguishable high omeprazole concentration in blood and the increased AUC were observed. These 6 subjects were distinguished as the CYP2C19 deficiency subjects. This frequency of poor metabolizer was similar as reported previously. On these subjects, trimethadione metabolic capacities were distributed unimodally. Furthermore, trimethadione metabolism in human hepatic microsomes were also performed with several selective CYPs inhibitors. In this condition, trimethadione metabolism was potently inhibited by chlorzoxazone, CYP2E1 substrate, and fluconazole, CYP3A4 inhibitor. These results indicate that trimethadione metabolism is mainly mediated by CYP2E1 and slightly by CYP3A4. These results suggest that omeprazole will be able to use for the CYP2C19 phenotyping by employing the blood samples 2 and/or 3hr after oral administration. On the other hand, trimethadione will be one of the probe drug for the estimation of human CYP2E1 activity in vivo. Less