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

Clin Chim Acta. 2009 Oct;408(1-2):92-7. doi: 10.1016/j.cca.2009.07.017. Epub 2009 Aug 3.


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)).

Conclusion: CL(m(6 beta)) cannot reflect the overall CYP3A activity accurately and quantitatively in the population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Female
  • Humans
  • Hydrocortisone / analogs & derivatives
  • Hydrocortisone / blood
  • Hydrocortisone / metabolism*
  • Hydrocortisone / urine
  • Hydroxylation
  • Male
  • Midazolam / administration & dosage
  • Midazolam / analogs & derivatives
  • Midazolam / blood
  • Midazolam / pharmacokinetics
  • Midazolam / urine
  • Phenotype*
  • Time Factors


  • 6 beta-hydroxycortisol
  • 1-hydroxymethylmidazolam
  • Cytochrome P-450 CYP3A
  • Midazolam
  • Hydrocortisone