Effect of Enteral Formulations on the Intestinal Absorption of Phenytoin in Rats

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The plasma concentration of phenytoin, when coadministered orally with an enteral formulation, is markedly decreased compared with that when phenytoin is administered alone. However, the mechanism behind this interaction has yet to be clarified. Here we tried to clarify the mechanism by rat intestinal loop perfusion method. Drug concentrations were measured by HPLC. Enteral formulations affected the intestinal absorption of phenytoin, but their inhibitory effects varied. Moreover, a good correlation was observed between the inhibitory effect and the osmotic pressure of the formulations. However, the lipid components in the formulations did not affect the absorption of phenytoin, and no effect on perfusate pH was recognized. These results indicate that the osmotic pressure of the enteral formulations affected the intestinal absorption of phenytoin. A defined formula containing various peptides had a greater inhibitory effect than that predicted from its osmotic pressure. The contribution of peptide transporters to the intestinal absorption of phenytoin was studied. Cephalexin and cephradine, as typical substrates of peptide transporters, markedly inhibited the absorption. These results indicate that osmotic pressure and peptides in the perfusate were the major factors responsible for the inhibitory effects of the enteral formulations on the intestinal absorption of phenytoin.
日本医療薬学会の論文