Inhibitory effects of cimetidine ketoconazole and miconazole on the metabolism of praziquantel.
In order to find ways to increase the usually very low bioavailability of praziquantel, the effect of cytochrome P-450 inhibitors on the metabolism of praziquantel was investigated in rats. Cimetidine, ketoconazole, and miconazole yielded a 90% inhibition of the metabolism of praziquantel in liver microsome preparations from phenobarbital-pretreated rats at concentrations of 2.0, 0.03, and 0.01 mM, respectively. In rats in vivo ketoconazole and miconazole increased the bioavailability of praziquantel by a factor of 2 and 4, respectively in doses of 25 mg/kg. In phenytoin-pretreated rats ketoconazole increased the bioavailability of praziquantel by a factor of 1.4, whereas miconazole yielded a 5-fold increase of the bioavailability. Cimetidine was an effective inhibitor at a dose of 200 mg/kg. These results suggest that the inhibitors tested may suppress the metabolism of praziquantel in humans and consequently increase the bioavailability and blood levels at doses common in human therapy.
Diekmann
H W
HW
Instititut für Experimentelle Arzneimittelforschung, E. Merck, Darmstadt, W. Germany.
Schneidereit
M
M
Overbosch
D
D
D000818:Animals; D001682:Biological Availability; D002927:Cimetidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D011223:Praziquantel / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D011223:Praziquantel; D008825:Miconazole; D002927:Cimetidine; D007654:Ketoconazole