Praziquantel: mode of action.

Praziquantel (PZQ) (Biltricide, Droncit) is a broadly effective trematocide and cestocide; data on its chemistry, pharmacokinetics and therapeutic efficacy against parasites in hosts including man have been recently reviewed by Andrews et al. (1983). PZQ is chemically unrelated to other antischistosomal drugs and possesses unique properties. PZQ has been shown to be effective against trematodes (e.g. Schistosoma, Paragonimus, Clonorchis, Opisthorchis, Metagonimus, Heterophyes) of man and animals independent of their location within the host body. Parasites living in the blood are almost equally susceptible to the drug as those in the intestine, lung or liver. All adult cestodes (e.g. Taenia, Hymenolepis, Diphyllobothriurn. Mesocestoides) and many larval cestodes can be successfully treated with PZQ; however, PZQ is not effective against nematodes. The reason is presumably the impervious cuticle of the nematodes, which is very different from the syncytial tegument of trematodes and cestodes which has absorptive functions. The pharmacokinetics of PZQ have been extensively studied and reviewed by Andrews (1985). After oral administration 80-100% of PZQ is absorbed. The invasion half-life varies from 0.1 to 0.3 h. In man, maximal serum concentrations of unchanged drug of 0.84. 1 PM are reached 1-3 h after application of an oral dose of 2&50mg/kg, respectively. PZQ is subjected to a pronounced first-pass metabolism. In rats, up to 74% of the drug is metabolized within 5min. Only 26% remains unchanged and this fraction rapidly disappears. PZQ is very rapidly distributed throughout all organs, with the highest concentrations occurring in the liver and the kidneys. Peak concentrations of PZQ after oral administration of equally effective doses to mouse and man ( > 95% parasite reduction or > 95% egg reduction) are reached after 5 min and after 1-3 h, respectively. Elimination in rats, dogs, monkeys and sheep is mainly renal (6&8OO/, of the excreted portion), while 15-37% is found in the bile and 6% is excreted into the intestinal lumen. Within 32 h 70-90% of an orally administered dose has been cleared from the body. PZQ itself is the active molecule requiring no metabolic alteration in order to become effective. Metabolic transformations by the host always result in less active or inactive metabolites. The therapeutic potency of PZQ can be increased by application of multiple oral doses at short intervals. The total amount of drug required to produce comparable parasite reduction in mice can be reduced by more than 70%: 10 doses of 18.5 mg/kg each every hour instead of one dose of 685 mg/kg. Thus the antischistosomal effect is not related to the absolute height of the maximal plasma concentrations, but rather to the length of exposure to the drug, i.e. PZQ follows a threshold/time model rather than a peak height model. Studies in vivo and in vitro indicate that the threshold concentration is somewhere between 0.32 and l . O p ~ , and this PZQ concentration is reached in man after application of curative drug doses. Schistosoma mansoni takes up PZQ rapidly. The concentration inside the parasite equals that in the medium within 2 min and increases further with time. Drug uptake is reversible and not dependent on the Ca2+ concentration of the external medium. PZQ appears to be distributed equally throughout the parasite tissues and there is no formation of metabolites in the parasite.