Two studies were conducted in healthy volunteers to evaluate the effects of rifampicin and cimetidine on the pharmacokinetics of the oral antimigraine compound zolmitriptan. Each study was an open, randomised, two-period crossover design. Rifampicin 600mg was administered daily for 8 days and cimetidine 400mg was administered three times daily for 2 days. In the control periods, no treatment was given. A single 5mg oral dose of zolmitriptan was given on the last day of each period. Enzyme induction by rifampicin was monitored using 6-beta hydroxycortisol/cortisol ratios. Rifampicin resulted in small (<18%), clinically insignificant decreases in the mean area under the plasma concentration-time curve (AUC), maximum plasma concentration (C(max)) and elimination half-life (t((1/2))) of zolmitriptan and its active metabolite, 183C91. Cimetidine, however, inhibited the metabolism of zolmitriptan and 183C91, increasing the mean C(max) by 16 and 50%, respectively, and increasing the mean AUC by 48 and 105%, respectively. Mean t((1/2)) was prolonged by 2.2 hours for zolmitriptan and by 4.2 hours for 183C91. The tolerability of zolmitriptan was unaltered when it was administered with either drug. Cytochrome 1A2 is likely to be the isoenzyme responsible for the metabolism of zolmitriptan. The increased exposure to zolmitriptan and 183C91 by cimetidine indicated that a reduction in the total daily recommended dose of zolmitriptan may be necessary when treating migraine patients who are taking nonspecific cytochrome P450 inhibitors or specific cytochrome 1A2 inhibitors.