title: Prodrugs of thiabendazole with increased water-solubility.
abstract: The poor peroral absorption of benzimidazole anthelmintics limits their usefulness for the treatment of systemic infections such as alveolar or cystic echinococcosis. The low bioavailability has mainly been attributed to the low aqueous solubility of the benzimidazoles. Using thiabendazole as a model compound the prodrug approach was investigated as a mean to obtain derivatives with improved water-solubilities. Bioreversible 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-acyloxymethyl derivatives were readily hydrolyzed to thiabendazole in human plasma and in rat and pig liver homogenates. The pH-rate profiles for the hydrolysis of the derivatives were determined and the lipophilicity of the compounds was assessed by partition experiments. The water-solubility of the N-alkoxycarbonyl derivatives was up to 12 times higher than that of the parent drug. An N-(4-amino-methylbenzoyl)oxymethyl derivative possessed a 300-fold higher water-solubility. The improved aqueous solubility, adequate lipophilicity and chemical stability combined with a facile enzymatic hydrolysis make such derivatives promising prodrugs for benzimidazole anthelmintics with the aim of improving the peroral bioavailability.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen.
authors.forename: L S
authors.initials: LS
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.forename: E
authors.initials: E
authors.lastname: Falch
mesh_terms: D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013827:Thiabendazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D011355:Prodrugs; D013827:Thiabendazole