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

Autor: Gravel S; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.; CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada., Chiasson JL; CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.; CHUM, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.; Faculty of Medicine, Université of Montréal, Montréal, Québec, Canada., Gaudette F; CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada., Turgeon J; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.; CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada., Michaud V; Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.; CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2019 Oct; Vol. 106 (4), pp. 831-840. Date of Electronic Publication: 2019 Jun 05.
DOI: 10.1002/cpt.1472
Abstrakt: 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 (r s  = 0.64 and 0.48; P ≤ 0.003) and 4β-OHC ratio (r s  = 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 (× 10 4 ); 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.
(© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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