Activity of Praziquantel Enantiomers and Main Metabolites against Schistosoma mansoni

Abstract

A racemic mixture of R and S enantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though the S enantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth sideby-side studies are lacking. The aim of this study was to investigate the in vitro activities of PZQ and its main metabolites, namely, R-and S-cis-and R-and S-trans-4=-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored the in vivo activity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations of R-PZQ, S-PZQ, and R-trans-and R-cis-4=-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 g/ml, respectively, for adult S. mansoni were determined in vitro. S-trans-and S-cis-4=-hydroxypraziquantel were not active at 100 g/ml. These results are consistent with microcalorimetry data and studies with NTS. In vivo, single 400-mg/kg oral doses of R-PZQ and S-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treated in vivo with S-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm that R-PZQ is the main effector molecule, while S-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ. S chistosomiasis or bilharzia is caused by blood flukes of the genus Schistosoma and is part of the group of neglected tropical diseases affecting more than 207 million people in tropical areas (1-3).The exclusive treatment to date for schistosomiasis is praziquantel (PZQ), which was discovered in the 1970s by Merck and Bayer. PZQ is administered as a racemic mixture of R and S enantiomers in tablets of 600 mg. The recommended dosage to treat schistosomiasis is 20 mg/kg three times in 1 day, and since PZQ does not act on juvenile worms, follow-up treatment 4 to 6 weeks later is strongly advised (4). In preventive chemotherapy programs, PZQ is administered as a single 40-mg/kg dose to at-risk populations (5). PZQ undergoes significant first-pass metabolism through the liver enzyme cytochrome P450 (CYP) 3A4 and to a lesser extent through 1A2 and 2C19 (6). R-PZQ is metabolized at a much higher rate than S-PZQ. R-PZQ is transformed mainly into cis-and trans-hydroxypraziquantel (4-OH-PZQ), while S-PZQ is converted to other monohydroxylated metabolites. In rat liver microsomes, the main metabolite is cis-4-OH-PZQ (7, 8), while in humans it is trans-4-OH-PZQ (9).The difference in the antischistosomal activity of each PZQ enantiomer has been known since 1983 (10), and several studies have observed greater activity of R-PZQ than of S-PZQ in vitro and in vivo (11)(12)(13). A clinical trial with Schistosoma japonicuminfected patients also recorded a higher efficacy of R-PZQ than of racemic PZQ at the same dosage (14, 15). Additionally, treatment with R-PZQ resulted in fewer adverse events than the standard treatment (14). However, ...

Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes

“…Significant worm burden reductions (P Ͻ 0.05) of 88.4% and 74.5% were observed for compounds 21 and 20, respectively. These values are comparable to the worm burden reduction observed with PZQ (32).…”

“…However, when their IC 50 s were compared to the IC 50 of the standard drug, praziquantel, these were more than an order of magnitude less potent in vitro. It is important to note that two of these three compounds were very effective in reducing the parasite burden in vivo, with the Fe 2ϩ complex being the most active (Table 3), showing activity comparable to that of praziquantel (32).…”

Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry

“…The data shown in Table 3 reveal a nonnegligible effect of OZ418 on adult S. mansoni (IC 50 of 18.3 to 27.4 g/ml or 44.2 to 66.2 M after 72 h), similar to that reported previously for juvenile and adult S. japonicum (IC 50 of 16 g/ml after 72 h) (39). However, these values are less impressive than the IC 50 s of praziquantel (0.08 to 0.16 M) in similar assays reported previously (66,67). As synthetic ozonides are suspected to act via an iron-dependent mechanism, we also evaluated the in vitro activity of OZ418 in the presence of red blood cells.…”

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Although the enzymes that metabolize PZQ1 are not fully known, PZQ1 is primarily metabolized by CYP 3A and to a lesser extent by CYP 2D6 (35). Several studies have been performed to clarify the metabolic profile of PZQ1, as well as the enzymes involved and the identities of the phase II metabolites (48)(49)(50)(51)(52)(53).…”