Evaluation of albendazole prodrugs in experimental trichinellosis

RESUMO

Background. Two albendazole (ABZ) prodrugs, N-methoxycarbonyl-N'-[(2-nitro-4-propylthio) phenyl] thiourea (compound 2), and N-methoxycarbonyl-N'-[2-nitro-5-propylthio) phenyl] thiourea (compound 3) have recently been synthesized. These compounds showed greater solubility than ABZ itself. Methods. In order to evaluate the biotransformation of compounds 2 and 3 to ABZ and/or ABZ-sulphoxide (ABZ-SO), plasma samples taken from mice treated with the prodrugs were analyzed by HPLC. Also, the anthelmintic activity of compounds 2 and 3 against Trichinella spiralis was evaluated in mice experimentally infected with the prarasite. Results. The presence of ABZ and/or ABZ-SO was demostrated in plasma samples taken at different time intervals after prodrug administration, although their levels were low compared to those reached in mice treated with ABZ. Additionally, prodrugs 2 and 3 were also detected in these samples. In regrad to the anthelmintic activity of ABZ prodrugs, it was shown that compound 3 was more active than compound 2. Additionally, it was as effective as ABZ against T. spiralis pre-adult, adult, and female fecundity. However, compound 3 was not as active sa ABZ against the muscle stage of the parasite. Conclusions. Compound 3 had better anthelmintic activity againts T. spiralis than compound 2. The bioconversion of compounds 2 and 3 to ABZ and/or ABZ-SO was demostrated by HPLC, but they did not reach equivalant concentrarion to that of ABZ. Prodrugs 2 and 3 were also present in plasma samples, suggesting that prodrugs were not efficiently reduced in the intestine of mice