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Poor correlation between 6β‐hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity
Author(s) -
Chen YaChi,
Gotzkowsky S. Karl.,
Nafziger Anne N.,
Kulawy Robert W.,
Rocci Mario L.,
Bertino Joseph S.,
Kashuba Angela D. M.
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02628.x
Subject(s) - cyp3a , midazolam , urinary system , endocrinology , medicine , urine , hydrocortisone , pharmacokinetics , chemistry , pharmacology , cytochrome p450 , metabolism , sedation
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 ( r 2 < 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.