A novel prodrug of salicylic acid, salicylic acid-glycylglycine conjugate, utilizing the hydrolysis in rabbit intestinal microorganisms

Article abstract of DOI:10.1111/j.2042-7158.1992.tb05505.x

The hydrolysis of salicylic acid-glycylglycine conjugate (salicyl-glycylglycine) following oral, intravenous, intracaecal and rectal administration (434, 72, 36 and 36 μmol kg ^-1, respectively: equivalent to salicylic acid) was examined in rabbits to develop a novel prodrug of salicylic acid. Salicylic acid was detected in thc blood 2 h after oral administration of salicyl-glycylglycine and it reached a maximum level (55-6 μg mL ^-1) at 15 h, whereas a small amount of salicyl-glycylglycine was found in the blood. In contrast, unchanged salicyl-glycylglycine was found mainly in the blood following its intravenous administration suggesting the involvement of presystemic deconjugation in the hydrolysis of salicyl-glycylglycine. Immediate and very extensive salicyclic acid formation in the caecum was observed following intracaecal administration of salicyl-glycylglycine, suggesting that the intestinal microorganisms were responsible for the biotransformation of this compound. In-vitro incubation of salicyl-glycylglycine with caecal content showed that salicyl-glycylglycine was hydrolysed efficiently in the caecum. Consequently, the blood concentration ol salicylic acid was prolonged extensively following rectal administration of salicyl-glycylglycine, indicating the usefulness of salicyl-glycylglycine as a prodrug of salicylic acid.