fluvoxamine and 6-beta-hydroxycortisol

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

Topics: Adult; Biomarkers; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Female; Fluvoxamine; Humans; Hydrocortisone; Injections, Intravenous; Liver; Male; Metabolic Clearance Rate; Midazolam; Phenotype