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

Abstract

Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

Keywords: cytochromes P450; enantiomers; metabolism; praziquantel; schistosomiasis.

FIG 1

The developmental cycle of S. mansoni, S. haematobium, and S. japonicum. Stages: A, paired adult worms (larger male enfolding slender female); B, eggs (left to right, S. haematobium, S. mansoni, and S. japonicum); C, ciliated miracidium; D, intermediate host snails (left to right, genera Oncomelania, Biomphalaria, and Bulinus); E, cercariae (infective stage).

FIG 2

Enantiomers of PZQ1 and biologically active (R-PZQ, PZQ2) and inactive (S-PZQ, PZQ3) isomers.

FIG 3

PZQ1 is metabolized by CYP 450, resulting in PZQ4 as the main product and other minor enantiomers such as PZQ5 and PZQ6. In addition, enantiomers of PZQ1 also undergo metabolism. Bold green and blue arrows indicate major metabolites of PZQ enantiomers PZQ2 and PZQ3, respectively. PZQ2 is mainly metabolized into trans- and cis-4-OH-PZQ (PZQ6), whereas PZQ3 is mainly metabolized into other mono- or dihydroxylated forms of PZQ1 and, to a less extent, into trans- and cis-4-OH-PZQ (PZQ5, PZQ6). P450 enzymes perform these transformations.

FIG 4

Structures of diverse PZQ derivatives developed and assessed for activity against schistosomes.

FIG 5

Metabolism of Cr-PZQ derivatives in vitro by human liver microsomes.