PRODRUGS OF THIABENDAZOLE WITH INCREASED WATER-SOLUBILITY

The poor peroral absorption of benzimidazole anthelmintics limits thei r usefulness for the treatment of systemic infections such as alveolar or cystic echinococcosis. The low bioavailability has mainly been att ributed to the low aqueous solubility of the benzimidazoles. Using thi abendazole as a model compound the prodrug approach was investigated a s a means to obtain derivatives with improved water-solubilities. Bior eversible derivatization of thiabendazole was performed by N-acylation of the benzimidazole moiety with various chloroformates as well as by N-acyloxymethylation. Both the N-alkoxycarbonyl and the N-acyloxymeth yl derivatives were readily hydrolyzed to thiabendazole in human plasm a and in rat and pig liver homogenates. The pH-rate profiles for the h ydrolysis of the derivatives were determined and the lipophilicity of the compounds was assessed by partition experiments. The water-solubil ity of the N-alkoxycarbonyl derivatives was up to 12 times higher than that of the parent drug. An N-(4-aminomethylbenzoyl)oxymethyl derivat ive possessed a 300-fold higher water-solubility. The improved aqueous solubility, adequate lipophilicity and chemical stability combined wi th a facile enzymatic hydrolysis make such derivatives promising prodr ugs for benzimidazole anthelmintics with the aim of improving the pero ral bioavailability.