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

Abstract

The relevance of endogenous 4β‐hydroxycholesterol (4β‐OHC) plasma concentrations or of the 4β‐OHC/total cholesterol concentration ratio (4β‐OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4β‐OHC (rs = 0.64 and 0.48; P ≤ 0.003) and 4β‐OHC ratio (rs = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4β‐OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4β‐OHC ratio (0.13 vs. 0.09 (× 104); P < 0.0002). These results suggest that 4β‐OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients.

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

“…The specificity of 4β‐OHC has been criticized for the lack of verification on its formation and clearance . In contrast, Gravel et al suggested that 4β‐OHC is considered as a suitable endogenous biomarker to evaluate CYP3A activity based on the strong correlation of plasma 4β‐OHC and 4β‐OHC/TC with midazolam metabolic ratio observed in patients. Thirdly, only one blood sample was collected for each patient in this study.…”

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

“…The impacts of genetics, gender, and to a limited extent, disease as factors contributing to interindividual variability in 4b-OHC have been investigated in adults (Mao et al, 2017). Recently, CYP3A activity was observed to be lower in type 2 diabetic compared to nondiabetic subjects, and this decrease was reflected in 4beta-OHC concentrations and 4beta-OHC/cholesterol ratio (Gravel et al, 2019). Based on 4b-OHC plasma concentrations in Swedes, Koreans, and Tanzanians, Diczfalusy et al reported interethnic differences in both CYP3A4 activity and the frequency of active CYP3A5*1 alleles (Diczfalusy et al, 2011).…”

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

“…There is therefore a need for the development of sensitive endogenous biomarkers, especially urinary biomarkers, as an alternative phenotyping method to overcome this challenge. Some endogenous compounds have been demonstrated to have potential as markers that mirror the interindividual variation of enzyme activities in drug metabolism [ 1 , 2 , 3 ]. The identification and validation of such endogenous markers could be useful in the evaluation of new chemical entities for the risk of drug-metabolising enzyme inhibition or induction-based DDI.…”