Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice.

ABSTRACT:

Purpose

This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice.

Methods

A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice.

Results

Uncertainty analysis demonstrated that the model structure

SUBMITTER: Edginton AN 

PROVIDER: S-EPMC4846505 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature