Development of quantitative prediction method for P450 induction

1999 Fiscal Year Final Research Report Summary

• Project/Area Number: 10672094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 医薬分子機能学
• Research Institution: Science University of Tokyo
• Principal Investigator: OKUDAIRA Kazuho Science Univ.of Tokyo, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 教授 (30204134)
• Co-Investigator(Kenkyū-buntansha): HAYASHI Masahiro Science Univ.of Tokyo, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20012669)
• Project Period (FY): 1998 – 1999
• Keywords: Enzyme induction / phenobarbital / omeprazole / cell culture / prediction / Hep G2 / 初代培養肝細胞

Research Abstract

In vitro-in vivo scaling works well for enzyme inhibition, but is less successful with enzyme induction. In this study, we attempt to predict in vivo enzyme induction from in vitro studies using primary cultured hepatocytes isolated from rats. Phenobarbital and omeprazole were used as a model inducer for CYP2B and CYP1A, respectively. We compared the in vitro with in vivo inducibility and constructed a kinetic model for quantitative prediction of the inducibility. Induction of CYP was observed in drug concentration and time-dependent manner. With single administration, CYP activity was induced dose-dependently. These results indicated that induction was related with both drug concentration and exposing time. We determined the average unbound concentration in plasma and maximum concentration, and compared them with those in culture medium. By this method, it was shown that inducibility calculated from in vitro studies well agreed with that in vivo. Although there still remains some problems for quantitative prediction, we showed possibility and effectiveness of prediction of enzyme inducibility in vivo from in vitro studies using cultured hepatocytes.