Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations.

ABSTRACT: An in vitro observation of time-dependent inhibition (TDI) of metabolic enzymes often results in removing a potential drug from the drug pipeline. However, the accepted method for predicting TDIs of the important drug metabolizing cytochrome P450 enzymes often overestimates the drug interaction potential. Better models that take into account the complexities of the cytochrome P450 enzyme system will lead to better predictions. Herein we report the use of our previously described models for complex kinetics of podophyllotoxin. Spectral characterization of the kinetics indicates that an intermediate MI complex is formed, which slowly progresses to an essentially irreversible MI complex. The intermediate MI complex can release free enzyme during the time course of a typical 30 min TDI experim

SUBMITTER: Barnaba C 

PROVIDER: S-EPMC5059843 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature