Simultaneous assessment of the in vivo amount of CYP1A2 and CYP3A2 by the PKCYP-test using theophylline in rats

摘要

Recently,we developed a method for assessing in vivo drug metabolism capacity by pharmacokinetic estimation of the quantity of cytochrome -450 (CYP) in vivo (PKCYP-test),in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced.The qg value can be alternatively defined as the ratio of te in vivo-invitro clearance by a single CYP isoform.In this study,we examined the application of the PKCYP-test to drugs metabolized by multiple CYP isoforms in a rat model with fluctuating CYP1A2 levels using theophylline as a model drug.In control rats,the estimated qg values for each CYP1A2 and CYP3A2 based on the in vivo hepatic intrinsic clearance,in vitro Michaelis constant (K_m)and maximal rate of metabolism(V_(max) values for liver slices agreed well.Moreover,the qg value for CYP1A2 determined by the K_m and V_(max) values for recombinant CYP1A2 was compatible with that based on liverslices.These qg values also agreed with that of rats pretreated with 3-methylcholanthrene.The time-course of theophylline concentrations in serum simulated by a physiologically-based pharamcokinetic model incorporating the hepatic clearance determined by the PKCYP-test agreed with the observed values.These results demonstrate that the qg value in the PKCYP-test is applicable to drugs metabolized by multiple CYP isoforms.