Perspective: 4β-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A

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.

Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

“…Multiple studies have evaluated cholesterol-based endogenous biomarkers of CYP3A activity in the presence of inducers or inhibitors in different patient cohorts. 21 However, very few evaluated the ability of 4β-OHC to characterize intrinsic CYP3A activities in patients with different diseases using a validated comparator. It has been shown that CYP450 activities are modulated by certain pathological conditions, especially when inflammation status is increased.…”

“…22,23 However, only few studies have measured 4β-OHC in different populations (e.g., patients with HIV, epilepsy, or gallstones) as an indicator of basal CYP3A4 activity before the administration of an inducer or an inhibitor. 21 Therefore, the objectives of this study were (i) to validate the use of both plasma 4β-OHC concentrations and 4β-OHC ratio (the molar ratio of 4β-OHC to total cholesterol plasma concentrations) as an endogenous biomarker of CYP3A activity in healthy subjects and (ii) to evaluate its reliability as a marker of CYP3A activity in a cohort of patients with type 2 diabetes (T2D). Midazolam was administered and used as a reference to validate 4β-OHC concentrations and ratio as biomarkers of basal CYP3A activity in our control and T2D populations.…”

“…Urinary 6β‐hydroxycortisol to cortisol ratio and plasma 4β‐hydroxycholesterol (4β‐OHC) to cholesterol ratio have been proposed as markers of CYP3A activities . In vivo determination of 4β‐OHC concentrations in the presence of CYP3A4 inducers and inhibitors as well as in vitro characterization of cholesterol metabolism using recombinant CYP450 isozymes confirmed that 4β‐OHC was the product of the CYP3A subfamily.…”

Impact of CYP3A5 genotype on tolvaptan pharmacokinetics and their relationships with endogenous markers of CYP3A activity and serum sodium level in heart failure patients

“…Both CYP3A4 and CYP3A5 mediate the cholesterol biotransformation to 4β-OHC. 17 In vitro metabolism of tolvaptan was faster using human liver microsomes with CYP3A5*1/*1 than with *1/*3 or *3/*3. 7 Our data indicate that tolvaptan is metabolized by CYP3A5 rather than CYP3A4 in human beings.…”

“…Plasma 4β-OHC as a non-P-glycoprotein activity marker has been utilized in a number of biomarker studies for predicting the pharmacokinetics of CYP3A probes and influences of CYP3A inducers. 17,18 Plasma 4β-OHC is also useful for the discrimination of patients with CYP3A5*3/*3. 13 Plasma 25-hydroxyvitamin D (25-OHD) is another promising biomarker of CYP3A activity.…”