Poor correlation between 6β-hydroxycortisol

cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

Chen, Ya-Chi
Gotzkowsky, S. Karl.
Nafziger, Anne N.
Kulawy, Robert W.
Rocci, Mario L. Jr.
Bertino, Joseph S. Jr
Kashuba, Angela D. M.

University of North Carolina, School of Pharmacy, Chapel Hill, NC, New York, NY, USA (Chen) (Gotzkowsky) (Kashuba)
¹Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York, NY, USA
²Prevalere Life Sciences, Whitesboro, New York, NY, USA

Correspondence Angela D. M. Kashuba BScPhm, PharmD, 3318 Kerr Hall, School of Pharmacy, CB♯7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Tel: + 1 919 962 0073 Fax: + 1 919 962 0644 E-mail: [email protected]

Received 8 November 2005 Accepted 29 December 2005 PublishedOnlineEarly 2 May 2006

British Journal of Clinical Pharmacology 62(2):p 187-195, August 2006.

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.