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

Clin Chim Acta. 2009 Aug 1; Hu ZY, Zhao YS, Wu D, Cheng ZNBACKGROUND: We determined if if endogenous cortisol 6beta-hydroxylation clearance [CL(m(6beta))] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activity). Methods: In 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 6beta-hydroxycortisol (6beta-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV). RESULTS: CL(m(6beta)) was poorly correlated (P>0.2) with MDZ oral clearance [CL(oral(MDZ))] and the ratio of AUC(0-infinity(1-OHMDZ)) versus AUC(0-infinity(MDZ)) [MR((AUC))]. However, when examining the data obtained from male volunteers exclusively, strong correlations were observed between CL(m(6beta)) and CL(oral(MDZ)). Larger interindividual and intraindividual variability was observed in urinary ratio of 6beta-OHF/F compared with CL(m(6beta)). Conclusion: CL(m(6beta)) can not reflect the overall CYP3A activity accurately and quantitatively in the population.