Simulations of Cytochrome P450 3A4-Mediated Drug-Drug Interactions by Simple Two-Compartment Model-Assisted Static Method

Abstract

In order to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs), a simple 2-compartment model-assisted, overall inhibition activity (A_i,overall) method was derived based on 2 concepts. One concept was that the increase in blood victim level and fold increase in the area under the blood victim level curve produced by DDI are determined entirely by A_i,overall, the hepatic availability of the victim and fraction of urinary excreted unchanged victim, where A_i,overall is determined by the perpetrator-specific CYP isoform inhibition activities (A_i,CYPs, DDI predictor-1) and victim-specific fractional CYP isoform contributions (f_m,CYPs, predictor-2). The other concept was that a DDI can be bridged to other DDIs, so that any possible DDI produced by a given victim or a given perpetrator can be predicted by using these predictors. The A_i,CYP3A4s of 12 common CYP3A4 inhibitors were able to be determined and shown to be useful for the prediction of CYP3A4-mediated DDIs wherein victims were metabolized by multiple CYP isoforms. Additionally, it was demonstrated that f_m,CYP values with high confidence can be estimated by bridging DDIs produced by the same victim and different perpetrators. This bridging approach will accelerate prediction of DDIs produced by new chemical entities from the existing DDI database.

Keywords: bioavailability; cytochrome P450; drug interaction; dynamic simulation; first pass metabolism; hepatic clearance; intestinal metabolism; parallel tube model; pharmacokinetics; simulations.