CHARACTERIZATION OF PRAZIQUANTEL METABOLISM BY RAT-LIVER MICROSOMES USING CYTOCHROME-P450 INHIBITORS

The metabolism of praziquantel (PZQ) was studied in microsomes isolate d from livers of differently pretreated rats and in the presence of va rious inhibitors of cytochrome P450 (P450) isoforms. Microsomes from p henobarbitone (PB)-pretreated rats metabolised PZQ to its major metabo lite 4OH-praziquantel (4OH-PZQ) at a greater rate than those from 20-m ethylcholanthrene (MC) and saline (SA) pretreated rats. The V-max 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-in ducible isoforms of P450. Inhibitor studies were conducted with micros omes from SA-pretreated animals. In these studies, caffeine, disulfura m, and tolbutamide were poor inhibitors of the metabolism of PZQ to 4O H-PZQ, with I-50 Values not determinable. Quinidine and quinine inhibi ted the hydroxylation of PZQ but with high K-i values. 17 alpha-Ethyny lestradiol, cimetidine and diphenylhydramine were effective inhibitors of the formation of 4OH-PZQ, with 17 alpha-ethynylestradiol being the most potent with a K-i of 0.5 +/- 0.05 mu M. From the known specifici ties of these P450 inhibitors, it is therefore concluded that cytochro mes P450 1A2, 2E1, 2C9-10, and 2D6 probably do not contribute signific antly 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 pre dominantly responsible for the formation of 4OH-PZQ.