N-ALKOXYCARBONYL PRODRUGS OF MEBENDAZOLE WITH INCREASED WATER SOLUBILITY

Bioreversible derivatization of mebendazole to improve its poor water solubility, which is attributed to its low peroral bioavailability, wa s performed by N-acylation of the benzimidazole moiety with various ch loroformates. The N-alkoxycarbonyl derivatives were readily hydrolyzed to mebendazole in rabbit liver homogenate and in human and rabbit pla sma. The pH-rate profiles for the hydrolysis of the derivatives were d erived at 37 degrees C, and the lipophilicity of the compounds was ass essed by partition experiments in octanol-aqueous buffer systems. The water solubility of the N-alkoxycarbonyl derivatives was up to 16-time s higher than that of the parent drug. The results obtained suggest th at N-alkoxycarbonyl derivatives of benzimidazole anthelmintics may be useful to improve the peroral bioavailability.