Endogenous cortisol 6β-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans

BackgroundWe determined if endogenous cortisol 6β-hydroxylation clearance [CLm(6β)] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activities).MethodsIn this study, 16 healthy volunteers received a single 7.5 mg oral dose of midazolam (MDZ). Blood samples were drawn up to 24 h after dosing. Urine samples were collected at various time periods after dosing. MDZ, 1-hydroxymidazolam (1-OHMDZ), cortisol (F) and 6β-hydroxycortisol (6β-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV).ResultsCLm(6β) was poorly correlated (P > 0.2) with MDZ oral clearance [CLoral(MDZ)] and the ratio of AUC0 − ∞(1 − OHMDZ) versus AUC0 − ∞(MDZ) [MR(AUC)]. However, when examining the data obtained from male volunteers exclusively, strong correlations were observed between CLm(6β) and CLoral(MDZ). Larger interindividual and intraindividual variabilities were observed in urinary ratio of 6β-OHF/F compared with CLm(6β).ConclusionCLm(6β) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.