Prodrug of diclofenac (DF-C2-P) was synthesized by introducing phospholipid-like compound into carboxyl group in the mother molecule. DF-C2-P was rapidly decomposed in neutral and alkaline solution while stable in acidic medium. A considerable increase of hydrolysis was observed in the PBS containing enzyme, porcine liver esterase, and diclofenac (DF) was produced as a result of enzymatic degradation of DF-C2-P. Plasma concentration of DF-C2-P and DF were analyzed after i v bolus injection in male Wistar rats, and four-compartment open model was applied to estimate pharmacokinetic parameters. Pharmacological activities of DF-C2-P was investigated with a tail-flick test and an acetic acid-induced writhing test in ddY mice. A significant enhancement in the antinociceptic action was observed by the administration of DF-C2-P, compared with that of DF. Gastric mucosal irritation was hardly observed when orally administered DF-C2-P in rats, suggesting that the prodrug prepared by introducing the phospholipid-like compound to the DF molecule may reduce ulcerogenic properties of DF.
