KURATA Norimitsu Showa University, School of Medicine, Dept.of Pharmacol., assistant professor, 医学部, 講師 (80231299)
UCHIDA Eiji Showa University, School of Medicine, Dept.of Pharmacol., associate professor, 医学部, 助教授 (80175223)
|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1994 : ¥1,400,000 (Direct Cost : ¥1,400,000)
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
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.