Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A. (2nd January 2017)

• Record Type: Journal Article
• Authors: Mao, Jialin; Martin, Iain; McLeod, James; Nolan, Gail; van Horn, Robert; Vourvahis, Manoli; Lin, Yvonne S.
• Is Part Of: Drug metabolism reviews. Volume 49:Number 1(2017)
• Page Start: 18
• Page End: 34
• Publication Date: 2017-01-02
• Subjects: 4?-Hydroxycholesterol -- CYP3A -- endogenous -- biomarker -- induction -- inhibition -- clinical -- drug development; Drugs -- Metabolism -- Periodicals; Pharmacokinetics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615
• DOI: 10.1080/03602532.2016.1239630
• Languages: English
• ISSNs: 0360-2532

Abstract

Abstract: A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug–drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4β-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4β-HC to evaluate changes in CYP3A activity has not been attempted. Herein, we review the biology of 4β-HC, its response to treatment with CYP3A inducers, inhibitors and mixed inducer/inhibitors in healthy volunteers and patients, the association of 4β-HC with other probes of CYP3A activity (e.g. midazolam, urinary cortisol ratios), and present predictive pharmacokinetic models. We provide recommendations for studying hepatic CYP3A activity in clinical pharmacology studies utilizing 4β-HC at different stages of drug development.