Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity.
OBJECTIVE
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.
Chen
Ya-Chi
YC
University of North Carolina, School of Pharmacy, Chapel Hill, NC 27599, USA.
Gotzkowsky
S Karl
SK
Nafziger
Anne N
AN
Kulawy
Robert W
RW
Rocci
Mario L
ML
Bertino
Joseph S
JS
Kashuba
Angela D M
AD
D000328:Adult; D015415:Biomarkers / Q000097:blood*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine*; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood*; D010641:Phenotype
D015415:Biomarkers; D065692:Cytochrome P-450 CYP3A Inhibitors; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; D016666:Fluvoxamine; D008874:Midazolam; D006854:Hydrocortisone