Experimental study on limited sampling strategy to predict metabolizing activity of hepatic CYP3A

Abstract

Abstract: AIM: To evaluate feasibility of a limited sampling strategy (LSS) in the prediction of inhibited hepatic CYP3A activity with systemic clearance of midazolam (MDZ), a phenotyping probe drug for hepatic CYP3A activity.METHODS: Linear regression analysis and a Jack-knife validation procedures were performed in one group of rats pretreated with a serial doses of ketoconazole, a selective inhibitor on CYP3A, as training set to establish the most informative LSS model for accurately estimating the clearance of MDZ. Another group of rats in same setting were used as validation set to estimate the individual clearance (Clest) based on predictive equations derived from the training set.RESULTS: LSS models derived from two or three sampling time points, including 60 and 90 min, 30, 60 and 90 min and 30, 60 and 120 min, exhibited best correlation and acceptable errors between Clobs and Clest were chosen to evaluate to hepatic CYP3A activity.CONCLUSION: The results indicated that limited plasma sampling for predicting systemic clearance of MDZ is a less complicated method to evaluation of CYP3A phenotyping when the activity of hepatic CYP3A was inhibited.The present study provided theoretical basis and laboratory evidence for LSS to clinically evaluate metabolizing function of liver and design rational drug regimen.

Key words: limited sampling strategy, hepatic, CYP3A, midazolam, ketoconazole

CLC Number:

R969

ZHU Xue-hui, LOU Jian-shi, JIAO Jian-jie, ZHANG Cai-li, LIU Chang-xiao. Experimental study on limited sampling strategy to predict metabolizing activity of hepatic CYP3A[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(12): 1404-1410.

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