The metabolism of praziquantel (PZQ) was studied in microsomes isolated from livers of differently pretreated rats and in the presence of various inhibitors of cytochrome P450 (P450) isoforms. Microsomes from phenobarbitone (PB)-pretreated rats metabolised PZQ to its major metabolite 4OH-praziquantel (4OH-PZQ) at a greater rate than those from 20-methylcholanthrene (MC) and saline (SA) pretreated rats. The Vmax for the PB microsomes was 600 nmol 4OH-PZQ formed/mg/min x 10(-3) compared to 91.4 nmol/mg/min x 10(-3) for MC and 238 nmol/mg/min x 10(-3) for SA microsomes. These results indicate that PZQ is metabolised by PB-inducible isoforms of P450. Inhibitor studies were conducted with microsomes from SA-pretreated animals. In these studies, caffeine, disulfuram, and tolbutamide were poor inhibitors of the metabolism of PZQ to 4OH-PZQ, with I50 values not determinable. Quinidine and quinine inhibited the hydroxylation of PZQ but with high Ki values. 17 alpha-Ethynylestradiol, cimetidine and diphenylhydramine were effective inhibitors of the formation of 4OH-PZQ, with 17 alpha-ethynylestradiol being the most potent with a Ki of 0.5 +/- 0.05 microM. From the known specificities of these P450 inhibitors, it is therefore concluded that cytochromes P450 1A2, 2E1, 2C9-10, and 2D6 probably do not contribute significantly to the metabolism of PZQ to its major metabolite in rats. It is likely that cytochromes P450 2B1 and 3A, both inducible by PB, are predominantly responsible for the formation of 4OH-PZQ.