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- Title
Poor correlation between 6β-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity.
- Authors
Ya-Chi Chen; Gotzkowsky, S. Karl.; Nafziger, Anne N.; Kulawy, Robert W.; Rocci, Mario L.; Bertino, Joseph S.; Kashuba, Angela D. M.
- Abstract
Aims A non-invasive proposed method for measuring CYP3A activity is the urinary 6β-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 6β-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity. Results No significant correlations were found between these two markers ( r2 < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6β-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.
- Subjects
HYDROCORTISONE; BIOMARKERS; BIOCHEMISTRY; BENZODIAZEPINES; MIDAZOLAM
- Publication
British Journal of Clinical Pharmacology, 2006, Vol 62, Issue 2, p187
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2006.02628.x