Oral administration of a low dose of midazolam (75 μg) as an in vivo probe for CYP3A activity

We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micr...

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Published in:European journal of clinical pharmacology 2004-06, Vol.60 (4), p.237-246
Main Authors: EAP, Chin B, BUCLIN, Thierry, KERB, Reinhold, CUCCHIA, Gianni, ZULLINO, Daniele, HUSTERT, Elisabeth, BLEIBER, Gabriela, POWELL GOLAY, Kerry, AUBERT, Anne-Catherine, BAUMANN, Pierre, TELENTI, Amalio
Format: Article
Language:English
Subjects:
Adult
Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors
Aryl Hydrocarbon Hydroxylases - biosynthesis
Aryl Hydrocarbon Hydroxylases - metabolism
Biological and medical sciences
Cross-Over Studies
Cytochrome P-450 CYP3A
Dose-Response Relationship, Drug
Enzyme Induction
Female
Humans
Ketoconazole - pharmacology
Male
Medical sciences
Midazolam - administration & dosage
Midazolam - adverse effects
Midazolam - analogs & derivatives
Midazolam - blood
Midazolam - pharmacokinetics
Middle Aged
Oxidoreductases, N-Demethylating - antagonists & inhibitors
Oxidoreductases, N-Demethylating - biosynthesis
Oxidoreductases, N-Demethylating - metabolism
Pharmacology. Drug treatments
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Summary:We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-004-0762-z