title: Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin.
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.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki, Finland.
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
authors.forename: M
authors.initials: M
authors.lastname: Ojala
authors.forename: H
authors.initials: H
authors.lastname: Laaksovirta
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005425:Flicker Fusion / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use*; D012890:Sleep / Q000187:drug effects
chemical_list: D002220:Carbamazepine; D010672:Phenytoin; D008874:Midazolam