4β‐Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation

Abstract

A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4β-hydroxycholesterol (4β-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal. Multiple studies in humans have shown that 4β-OHC can qualitatively differentiate among weak, moderate, and potent CYP3A induction when an inducer, typically rifampin, is administered for up to 2 weeks. Conversely, longer durations of CYP3A inhibitor administration (ࣙ1 month) appear to be necessary to differentiate among weak, moderate, and potent CYP3A inhibitors. A number of studies have reported statistically significant linear relationships between 4β-OHC plasma concentrations (and 4β-OHC:cholesterol ratios) and midazolam clearance. However, sufficiently powered studies assessing the ability of 4β-OHC or 4β-OHC:cholesterol ratios to measure CYP3A activity (ie, predictive performance) have not been conducted to date. Additional limitations associated with 4β-OHC phenotyping include inability to detect acute changes in CYP3A activity, uncertainty with regard to its intestinal formation, ambiguity surrounding the role of CYP3A5 in its metabolism, and lack of clarity regarding the role of transporters in its disposition. As such, the data do not support the use of 4β-OHC or 4β-OHC:cholesterol ratios as an endogenous biomarker for CYP3A activity. Keywords4β-hydroxycholesterol, biomarker, cytochrome P450 (CYP)3A, drug interaction the European Medicines Agency as a sensitive index substrate for CYP3A metabolism. 8,9 Recently, plasma 4β-hydroxycholesterol (4β-OHC), which is the metabolite of CYP3A4/5-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A. 10,11 Further, 4β-OHC and 4β-OHC:cholesterol ratios have been suggested as a probe for CYP3A in the drug development process. 11 This review critically examines the use of 4β-OHC as a marker for CYP3A activity and assesses its potential utility for this purpose. Cholesterol and 4β-OHCCholesterol is biotransformed into oxysterols via several pathways including auto-oxidation and

The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam

“…Additional aspects studied were: (i) RIF's impact on the concentrations of sex hormone binding globulin (SHBG), a main binding protein for several progestins, among them LNG, NET, and DSG's active metabolite etonogestrel (ENG); and (ii) the association among changes in progestin, EE, and MDZ exposure and changes in the plasma concentrations of 4ß-hydroxycholesterol (4ß-HC), an endogenous biomarker of hepatic CYP3A activity. [11][12][13] METHODS The protocol for this study (EudraCT 2017-002792-26; clinicaltrials.gov NCT03353857) was approved by the relevant independent ethics committee before the start of the study (Ethics Committee of Nordrhein; reference number 101/17-03 RN). All subjects gave their written informed consent before entry into the study.…”

“…5,4,5,6,8,12,15,24, 48, 72, 96, 120, and 144 hours postdose (for MDZ only until 24 hours postdose). Plasma samples to determine RIF trough concentrations and 4ß-HC concentrations were taken on days 8, 10, 13, 15, 17, 19, and 28 before RIF intake and on day 30.…”

Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time

“…However, in this trial, it was noted that buccal absorption occurs within 2 minutes and therefore might circumvent first‐pass metabolism 11 . Midazolam is almost exclusively metabolized by CYP3A; due to first‐pass metabolism, the absolute bioavailability is low (20%‐25%), there is no involvement of drug transporters, and it has a short half‐life (3‐4 hours) 3,12,13 . To have a reliable and reproducible phenotyping method with buccal microdosed midazolam, it is important to study the influence of midazolam exposure time in the oral cavity on first‐pass metabolism of midazolam.…”

“…11 Midazolam is almost exclusively metabolized by CYP3A; due to first-pass metabolism, the absolute bioavailability is low (20%-25%), there is no involvement of drug transporters, and it has a short half-life (3-4 hours). 3,12,13 To have a reliable and reproducible phenotyping method with buccal microdosed midazolam, it is important to study the influence of midazolam exposure time in the oral cavity on firstpass metabolism of midazolam. The aim of the study was to assess the absolute bioavailability of microdosed midazolam after buccal administration in relation to the buccal exposure time and compare it with oral administration.…”

Phenotyping Cyp3a4/5 Using an Endogenous Biomarker in Children With Down Syndrome

“…In this context, the metabolite of cholesterol e.g. 4β-OHC reflects the activity of CYP3A4/5 so it was utilized as an endogenous biomarker for phenotyping of activity of these enzymes [14][15][16] . Studies deals with phenotyping Cytochrome P450 in DS are very limited.…”