Cefpodoxime proxetil esterase activity in rabbit small intestine: A role in the partial cefpodoxime absorption

The luminal and mucosal de-esterification of the prodrug ester cefpodoxime proxetil was studied in rabbit intestine in vitro. An enzymatic hydrolysis of the ester, releasing the active third-generation cephalosporin, was observed in both luminal washing and mucosal homogenate. The mucosal activity was mainly recovered in the soluble fraction, whereas the brush-border membranes were almost devoid of activity. Eserine and diisopropyl fluorophosphate were potent inhibitors of cefpodoxime proxetil hydrolysis in both luminal washing and mucosal homogenate, suggesting the participation of choline esterases in the hydrolysis of cefpodoxime proxetil. The luminal and mucosal activities were equally sensitive to HgCl2 and acetylsalicylic acid inhibitions but slight differences were observed concerning the 50% inhibitory concentration (IC50) of two drug esters, bacampicillin and enalapril. In vitro experiments run with rabbit jejunum mounted in Sweetana-Grass diffusion chambers showed that an extensive hydrolysis of cefpodoxime proxetil occurred in the mucosal compartment and that the accumulation of cefpodoxime in the serosal compartment was very slow. These observations support the hypothesis that the partial oral bioavailability of cefpodoxime proxetil results from a hydrolysis by luminal choline esterases. (C) 1997 Elsevier Science B.V.