Activity of Praziquantel Enantiomers and Main Metabolites against Schistosoma mansoni

Abstract

ABSTRACTA racemic mixture ofRandSenantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though theSenantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth side-by-side studies are lacking. The aim of this study was to investigate thein vitroactivities of PZQ and its main metabolites, namely,R- andS-cis- andR- andS-trans-4′-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored thein vivoactivity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations ofR-PZQ,S-PZQ, andR-trans- andR-cis-4′-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 μg/ml, respectively, for adultS. mansoniwere determinedin vitro. S-trans- andS-cis-4′-hydroxypraziquantel were not active at 100 μg/ml. These results are consistent with microcalorimetry data and studies with NTS.In vivo, single 400-mg/kg oral doses ofR-PZQ andS-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treatedin vivowithS-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm thatR-PZQ is the main effector molecule, whileS-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ.