Comparison of endogenous 4ß-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin.
Drug Metab Dispos
; 41(8): 1488-93, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23674608
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 4ß-hydroxycholesterol with the midazolam clearance in plasma and the 6ß-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 4ß-hydroxycholesterol ratio (both P < 0.01), and the 6ß-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 4ß-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6ß-hydroxycortisol/cortisol ratio. In conclusion, the 4ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rifampina
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Midazolam
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Citocromo P-450 CYP3A
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Hidroxicolesteróis
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article