Endogenous cortisol 6 beta-hydroxylation clearance is not an accurate probe for overall cytochrome P450 3A phenotyping in humans.
BACKGROUND
We determined if endogenous cortisol 6 beta-hydroxylation clearance [CL(m(6 beta))] could be used as a reliable index for in vivo CYP3A phenotyping (including both hepatic and intestinal CYP3A activities).


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 6 beta-hydroxycortisol (6 beta-OHF) in plasma or urine were determined by high-performance liquid chromatography with ultraviolet absorbance detection (HPLC-UV).


RESULTS
CL(m(6 beta)) 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(6 beta)) and CL(oral(MDZ)). Larger interindividual and intraindividual variabilities were observed in urinary ratio of 6 beta-OHF/F compared with CL(m(6 beta)).


CONCLUSIONS
CL(m(6 beta)) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.
Hu
Zhe-Yi
ZY
Shanghai Institute of Materia Medica and Graduate School, Chinese Academy of Sciences, Shanghai 201203, PR China. huzheyi_99@hotmail.com
Zhao
Yuan-Sheng
YS
Wu
Di
D
Cheng
Ze-Neng
ZN
D000284:Administration, Oral; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006900:Hydroxylation; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D010641:Phenotype; D013997:Time Factors
C001380:6 beta-hydroxycortisol; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D006854:Hydrocortisone