Feasibility of cisapride as an in vivo probe of CYP3A activity in rats

• Main Authors: Mei-sien Kuan, 官玫仙
• Other Authors: Ching-Ling Cheng
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/71792154336026857468

碩士 === 國立成功大學 === 臨床藥學研究所 === 95 === Introduction. Variability in drug response can be attributed in part to variability in the activity of drug-metabolizing enzymes. Measuring in vivo enzyme activity by probe drugs can therefore provide valuable information for managing variability in drug response. The prokinetic agent cisapride is metabolized primarily by CYP3A and it is not a substrate of Pgp. The applicability of cisapride as a probe substrate to assess in vivo CYP3A activity in humans has been demonstrated recently. And the 8-hr plasma concentration of cisapride after a single oral dose has been served as a predictor of its clearance. Purpose. In this study, the applicability of a single cisapride plasma concentration as in vivo probe for CYP3A in rats was investigated following intravenous administration of cisapride. Methods. Rats received cisapride (1, 3, 5, 7.5 or 10 mg/kg) in the dose-linearity control groups. And in the CYP3A modulation groups, rats received 5 mg/kg cisapride after pretreatment with dexamethasone (induction), ketoconazole (inhibition), or erythromycin (inhibition). The plasma concentrations of cisapride were followed for 480 min, and the kinetic parameters were estimated by non-compartmental analysis. The contents of CYP3A2 in hepatic microsomes of rats were measured by western blotting analysis. Results. Optimal correlations between area under concentration-time curve (AUC) and plasma concentration in the control groups were at 150, 40, 40, 150, and 150 min for the 1, 3, 5, 7.5 or 10 mg/kg dosing groups, respectively. In the CYP3A modulation groups, correlation for the induction and inhibition groups were both optimal at 40 min. In the composite analysis of all treatments, optimal correlation occurred at 90 min. The hepatic CYP3A2 contents of rats also showed linear correlation with cisapride AUC. Conclusion. A single 90-min plasma concentration following intravenous administration of cisapride can predict its AUC and hence clearance in rats. Therefore, this approach represents an effective method for assessing in vivo CYP3A activity.