| Summary: | 碩士 === 國立成功大學 === 臨床藥學與藥物科技研究所 === 100 === Introduction
CYP3A is one of the most important and most abundant subfamily expressed in the liver and small intestine. The use of selected drugs as “probes” to assess in vivo CYP activity has been the subject of intense interest for over a decade. Among many CYP3A probes, midazolam is the most accepted CYP3A probe used in human, but it’s use is limited.
Mosapride, a new prokinetic agent, undergoes N-dealkylation metabolism to form des-4-fluoro-benzyl metabolite （M-1) mediated by CYP3A enzymes.After intravenous and oral administration of mosapride, the hepatic and intestinal CYP3A contents showed strongly correlation with mosapride, therefore, mosapride clearance can be used to reflect the in vivo CYP3A activity,on the other hand, strong correlation between the clearance of mosapride and midazolam supports the applicability of mosapride as a probe to assess hepatic CYP3A activity in rats.
Purpose
In this project, it is aimed to characterize the in vitro microsome kinetics of mosapride itself and inhibition kinetics with other known CYP3A inhibitors. Finally, to evaluate the feasibility of mosapride to predict CYP3A-mediated drug-drug interactions in rats.
Methods
In vitro experiment, the incubation system and kinetic parameters of the substatrates（Km, Vmax）will be established,.The inhibition constant（Ki or IC50） of typical CYP450 inhibitors will be determined and compared with reference values. In vitro/in vivo extrapolation（IVIVE）equation and in vitro/in vivo scaling technique were used to predict the decrease in CL of mosapride after ketoconazole IV infusion treatment. Thus to evaluate the feasibility of mosapride to predict enzyme inhibition effect of ketoconazole by comparing the prediction from in vitro data with in vivo drug-drug interactions data.
Results
From in Vitro studies it comfirmed that mosapride is primarily metabolized by CYP3A subfamily in rats. We found mosapride is not only the substrate but also acts as an inhibitor on midazolam metabolism（Ki =3.8 μM）.And as a probe substrate, mosapride reflected enzymes activity well in inhibition conditions. Finally, clearance of mosapride affected by ketoconazole is well-predicted by using IVIVE equation and IVIV scaling technique.
Conclusions
Results in this studies provide more evidence on the applicability of mosapride as a potential in vitro and in vivo hepatic CYP3A probe used to assess aspects of drug interactions having potential clinical importance in rat model, and may helpful to evaluate CYP3A related drug-drug , drug-herb, and drug food interactions in drug development and in clinical application.
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