CEFPODOXIME-PROXETIL HYDROLYSIS AND FOOD EFFECTS IN THE INTESTINAL LUMEN BEFORE ABSORPTION - IN-VITRO COMPARISON OF RABBIT AND HUMAN MATERIAL

The luminal and mucosal deesterification of the prodrug ester cefpodox ime-proxetil was studied in human duodenal washings in vitro. Enzymati c hydrolysis of the ester, releasing the active third generation cepha losporin, was observed in luminal washing in the same way as it had pr eviously been observed in the rabbit. Eserine and PMSF and HgCl2 were potent inhibitors of cefpodoxime-proxetil hydrolysis in luminal washin g, suggesting the participation of a cholinesterase in the hydrolysis of cefpodoxime-proxetil. These results are in agreement with our previ ous findings performed in the rabbit. Moreover, cefpodoxime-proxetil d irectly decreases the acetylcholinesterase activity when tested by a s pecific enzymatic method. These observations support the hypothesis th at the partial oral bioavailability of cefpodoxime-proxetil results fr om hydrolysis by luminal cholinesterases. In vitro experiments run wit h rabbit duodenal washing with food components were compared with the pharmacokinetics of cefpodoxime-proxetil in humans. Amino acids, trace elements and vitamins were potent inhibitors for cefpodoxime-proxetil hydrolysis in duodenal washings. Otherwise, lipids (LTC and mixed LCT /MCT) did not interact. In the human, cefpodoxime-proxetil bioavailabi lity is significantly enhanced when tablets are administered with food . The correlation found between animal results and human results in vi tro for prospective investigation of a new prodrug ester could be very useful. An in vitro hydrolysis in intestinal animal washings could al low the potentially degraded condition and the food effect of the lumi nal tract to be assessed before absorption. (C) 1997 Elsevier Science B.V.