Abstract
CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P < 0.01), and the 6β-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.
Footnotes
- Received April 9, 2013.
- Accepted May 14, 2013.
The study was financially supported by AstraZeneca, Sweden; and with grants from Swedish Research Council (No. 3902); the Swedish Foundation for Clinical Pharmacology and Pharmacotherapy; and through the regional agreement on training and clinical research (ALF) between Karolinska Institutet and Stockholm County Council.
L.B.-B. holds a postdoctoral financed by Karolinska Institutet and Stockholm County Council (KI/SLL). T.B.A. and E.B. are employees of AstraZeneca. Unrestricted financial support was provided by AstraZeneca. This has not influenced the design or the interpretation of the results of this study.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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