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 cefpodo xime proxetil was studied in rabbit intestine in vitro. An enzymatic h ydrolysis of the ester, releasing the active third-generation cephalos porin, was observed in both luminal washing and mucosal homogenate. Th e mucosal activity was mainly recovered in the soluble fraction, where as 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, su ggesting the participation of choline esterases in the hydrolysis of c efpodoxime proxetil. The luminal and mucosal activities were equally s ensitive to HgCl2 and acetylsalicylic acid inhibitions but slight diff erences were observed concerning the 50% inhibitory concentration (IC5 0) of two drug esters, bacampicillin and enalapril. In vitro experimen ts run with rabbit jejunum mounted in Sweetana-Grass diffusion chamber s showed that an extensive hydrolysis of cefpodoxime proxetil occurred in the mucosal compartment and that the accumulation of cefpodoxime i n the serosal compartment was very slow. These observations support th e hypothesis that the partial oral bioavailability of cefpodoxime prox etil results from a hydrolysis by luminal choline esterases. (C) 1997 Elsevier Science B.V.