Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework.

ABSTRACT: Background/Objectives: Plasma levels of 4β-hydroxycholesterol (4β-OHC), a CYP3A-specific metabolite of cholesterol, are elevated after administration of CYP3A inducers like rifampicin and carbamazepine. To simulate such plasma 4β-OHC increase, we developed a physiologically based pharmacokinetic (PBPK) model of cholesterol and 4β-OHC in the Simcyp PBPK Simulator (Version 23, Certara UK Ltd.) using a middle-out approach. Methods: Relevant physicochemical properties and metabolic pathway data for CYP3A and CYP27A1 was incorporated in the model. Results: The PBPK model recovered the observed baseline plasma 4β-OHC levels in Caucasian, Japanese, and Korean populations. The model also captured the higher baseline 4β-OHC levels in females compared to males, indicative of sex

SUBMITTER: Karkhanis AV 

PROVIDER: S-EPMC11510160 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature