Abstract
Recently, we developed a method for assessing in vivo drug metabolism capacity by pharmacokinetic estimation of the quantity of cytochrome P450 (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 the in vivo-in vitro 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 liver slices. 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 pharmacokinetic 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.
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