Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe.
Int J Clin Pharmacol Ther
; 47(2): 111-9, 2009 Feb.
Article
en En
| MEDLINE
| ID: mdl-19203567
ABSTRACT
UNLABELLED Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe. OBJECTIVE:
The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated.METHODS:
This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted.RESULTS:
Apparent oral clearance was 2,030 +/- 651 and 1,939 +/- 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 - 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women.CONCLUSION:
i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.
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Banco de datos:
MEDLINE
Asunto principal:
Midazolam
/
Flumazenil
/
Moduladores del GABA
/
Citocromo P-450 CYP3A
Tipo de estudio:
Clinical_trials
Límite:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Int J Clin Pharmacol Ther
Asunto de la revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos