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Epilepsia. 1996 Mar;37(3):253-7.

Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin.

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1
Department of Clinical Pharmacology, University of Helsinki, Finland.

Abstract

Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacodynamic aspects of an oral 15-mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean +/- SEM) was only 5.7% (0.60 +/- 0.16 vs. 10.5 +/- 0.6 microgram x min/ml), and the peak midazolam concentration was 7.4% (5.2 +/- 1.2 vs. 70.4 +/- 9.0 ng/ml) of its value in control subjects (p < 0.001). The elimination half-life (t l/2) of midazolam was 1.3 +/- 0.2 h in patients and 3.1 +/- 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P-450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.

[Indexed for MEDLINE]

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