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

药物代谢酶多态性及药物疗效和安全性评价

基本信息

批准号：
06672277
负责人：
YASUHARA Hajime
金额：
$ 1.34万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672277/
关键词：
trimethadione omeprazole cytochorome P-450 genetic polymorphism hepatic drug metabolizing enzymes Trimethadione

项目摘要

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

在本项目中，我们建立了一种简单可靠的CYP2C19基因多态性缺失估计方法。在这十年中，CYP2C19缺乏症通过使用在日本未获批准的探针药物甲苯妥英（mephenytoin）来确定。s -甲苯妥英是CYP2C19最特异的底物，但用甲苯妥英进行CYP2C19的测定存在很多伦理问题。考虑到这些原因，我们选择了CYP2C19底物奥美拉唑作为探针药物。另一方面，甲美二酮已被用于测定人体内药物代谢酶的能力。该化合物在大鼠体内被CYP2E1、CYP2C和CYP3A亚家族代谢。然而，目前尚不清楚哪一种CYPs负责甲美二酮的代谢。为了明确甲美二酮和奥美拉唑将是CYP2C19表型分型的探测药物，本研究对38名健康受试者进行了研究。通过几个时间段后的血液样本来估计药物代谢能力。38名健康人奥美拉唑代谢活性呈双峰分布，6名健康人血中奥美拉唑浓度明显偏高，AUC升高。这6例患者均为CYP2C19缺乏症患者。这种代谢不良的频率与之前报道的相似。在这些受试者中，甲美二酮代谢能力呈单峰分布。此外，还用几种选择性CYPs抑制剂对人肝微粒体中的甲美二酮代谢进行了研究。在这种情况下，氯唑唑酮（CYP2E1底物）和氟康唑（CYP3A4抑制剂）有效地抑制了甲美二酮的代谢。这些结果表明，甲美二酮的代谢主要由CYP2E1介导，少量由CYP3A4介导。这些结果表明，奥美拉唑将能够通过口服给药后2和/或3小时的血液样本用于CYP2C19表型分析。另一方面，甲美二酮将成为估计人体内CYP2E1活性的探针药物之一。少