Pharmacokinetics and microsomal oxidation of praziquantel and its effects on the P450 system in three-month-old lambs infested by Fasciola hepatica

Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine. In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica. Foll owing both oral and i.m. administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimina tion. Although the PZQ dose used by the i.m. route was only half of that us ed by the oral route, the mean PZQ plasma concentration was higher after i. m. than after oral treatment. Oral treatment with 30 mg/kg/day of PZQ did n ot modify the mono-oxygenase activities tested, whilst the administration o f PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6 beta testosterone h ydroxylase activities. From the incubation of microsomes from lambs not tre ated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis. By selective inhibition of the 3A subfamily performed wi th triacetyloleandromycin, the production of this metabolite declined by ab out 90% suggesting a prominent role of P450 3A isoforms in this oxidation. These features indicate that agents or drugs which are able to modulate P45 0 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ.