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

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Serval ID
serval:BIB_9381D46D9A28
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.
Journal
European journal of clinical pharmacology
Author(s)
Eap C.B., Buclin T., Cucchia G., Zullino D., Hustert E., Bleiber G., Golay K.P., Aubert A.C., Baumann P., Telenti A., Kerb R.
ISSN
0031-6970
Publication state
Published
Issued date
2004
Peer-reviewed
Oui
Volume
60
Number
4
Pages
237-46
Language
english
Notes
Publication types: Clinical Trial ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.
Keywords
Adult, Aryl Hydrocarbon Hydroxylases, Cross-Over Studies, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Enzyme Induction, Female, Humans, Ketoconazole, Male, Midazolam, Middle Aged, Oxidoreductases, N-Demethylating
Pubmed
Web of science
Open Access
Yes
Create date
10/03/2008 11:38
Last modification date
01/10/2019 7:18
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