Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Clin Pharmacol Ther. 2019 Oct;106(4):831-840. doi: 10.1002/cpt.1472. Epub 2019 Jun 5.
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 = 0.64 and 0.48; P ≤ 0.003) and 4β-OHC ratio (r = 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 ); 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.
评估内源性 4β-羟胆固醇（4β-OHC）血浆浓度或 4β-OHC/总胆固醇浓度比值（4β-OHC 比值）作为细胞色素 P450 3A（CYP3A）活性替代标志物在 2 型糖尿病（T2D）患者（n=38）或非 T2D 患者（n=35）中的相关性。以咪达唑仑作为表型 CYP3A 活性的验证性指标。非糖尿病和糖尿病人群中口服给予咪达唑仑的代谢比值与 4β-OHC（r=0.64 和 0.48；P≤0.003）和 4β-OHC 比值（r=0.69 和 0.46；P≤0.003）呈显著相关性。与非糖尿病受试者相比，T2D 患者 CYP3A 活性较低；这一降低反映在 4β-OHC 浓度（24.33 对 12.58ng/mL；P<0.0001）和 4β-OHC 比值（0.13 对 0.09（×10）；P<0.0002）中。这些结果表明，4β-OHC 可作为 CYP3A 活性的有效、方便、易于使用的内源性生物标志物在患者中考虑。
