Concentrations and Effects of Oral Midazolam are Greatly Reduced in Patients Treated with Carbamazepine or Phenytoin

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Abstract
Summary: Midazolam is a short‐acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacody‐namic 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 2 SEM) was only 5.7% (0.60 ± 0.16 vs. 10.5 ± 0.6 μg ‐ min/ml), and the peak midazolam concentration was 7.4% (5.2 ± 1.2 vs. 70.4 ± 9.0 μg/ml) of its value in control subjects (p < 0.001). The elimination half‐life (t1/2) 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.