Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

Br J Clin Pharmacol. 2006 Aug;62(2):187-95. doi: 10.1111/j.1365-2125.2006.02628.x.


Aims: A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor.

Methods: This was a sequential, cross-over study design. Intravenous midazolam 0.025 mg kg(-1) was administered to 10 male and 10 female subjects once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity.

Results: No significant correlations were found between these two markers (r(2) < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately 1.5-fold and cortisol ratios decreased approximately 1.9-fold.

Conclusions: The high intra-individual variability of the urinary cortisol ratio, compared with midazolam, makes this a suboptimal CYP3A phenotyping tool.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors
  • Female
  • Fluvoxamine / pharmacology
  • Humans
  • Hydrocortisone / analogs & derivatives*
  • Hydrocortisone / urine*
  • Injections, Intravenous
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Metabolic Clearance Rate
  • Midazolam / administration & dosage
  • Midazolam / blood*
  • Phenotype


  • Biomarkers
  • Cytochrome P-450 CYP3A Inhibitors
  • 6 beta-hydroxycortisol
  • Cytochrome P-450 CYP3A
  • Fluvoxamine
  • Midazolam
  • Hydrocortisone