Quantitative Prediction of CYP3A4- and CYP3A5-Mediated Drug Interactions.

ABSTRACT: We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics-informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (F_G ) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework

SUBMITTER: Guo Y 

PROVIDER: S-EPMC6925622 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature