THE EFFECT OF THE ANTIMYCOTIC ITRACONAZOLE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DIAZEPAM

The azole antimycotic itraconazole is a potent and relatively unspecif ic inhibitor of cytochrome P450 enzymes and has a potentially dangerou s interaction with midazolam and triazolom. the possible interaction b etween itraconazole and diazepam was investigated in a double-blind, r andomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma s amples were collected and psychomotor performance tests were carried o ut for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimi nation half-life of diazepam, there was no clinically significant inte raction as determined by the psychomotor performance tests. The lack o f significant first-pass metabolism adn the different metabolic pathwa ys of diazepam explain the smaller interaction as determined by the ps ychomotor performance tests. The lack of significant first-pass metabo lism and the different metabolic pathways of diazepam explain the smal ler interaction potential of diazepam compared with midazolam and tria zolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inh ibitors of P4503A4, at least when diazepam is used as single doses.