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

Abstract

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.

Figure 1

(a) Urinary 6β-hydroxycortisol:cortisol molar ratio at baseline and after treatment of fluvoxamine for men and women (the error bars indicate 5th and 95th percentile; circles indicate the outliers). (b) Midazolam plasma clearance at baseline and after treatment of fluvoxamine for men and women (the error bars indicate 5th and 95th percentile; circles indicate the outliers). Baseline () post treatment (□)

Figure 2

(a) Correlations between plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio for CYP3A phenotyping in all subjects at baseline (circles, women; squares, men). (b) Correlations between plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio for CYP3A phenotyping in all subjects post treatment (circles, women; squares, men). (c) Correlations between the changes of plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio (post treatment/baseline) for CYP3A phenotyping in all subjects (circles, women; squares, men)