Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis.

ABSTRACT: Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop physiologically based kinetic (PBK) models that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. We developed a PBK model describing the BA homeostasis using glycochenodeoxycholic acid as an exemplary BA. Population wide distributions of BSEP abundances were incorporated in the PBK model using Markov Chain Monte Carlo simulations, and alternatively the total amount of BAs was scaled empirically to describe interindividual

SUBMITTER: de Bruijn VMP 

PROVIDER: S-EPMC9352636 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature