Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe.
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.


CONCLUSIONS
i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.
Ma
J D
JD
Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, NY, USA. joema@ucsd.edu
Lawendy
N M
NM
Fullerton
T
T
Snyder
P J
PJ
Nafziger
A N
AN
Bertino
J S
JS
D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010641:Phenotype; D012737:Sex Factors; D013810:Therapeutic Equivalency
D018757:GABA Modulators; D005442:Flumazenil; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam