INTERACTIONS AFFECTING PHENYTOIN INTESTINAL

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The objective of the proposed research is to determine the extent to which coadministered glucose and calcium affect the intestinal absorption of the orally administered anticonvulsant, phenytoin, from solution. Phenytoin possesses a narrow therapeutic range and minor blood level fluctuations can result in dramatic clincial effects with respect to insufficient activity or effective overdosage. While the drug is well absorbed from solution, its poor dissolution and interactions with coadministered substances in the gastrointestinal (GI) tract can significantly affect its absorption. Two of these substances (glucose and calcium) apear to affect interactions at the intestinal membrane from phenytoin solution. Several reports in the literature and preliminary data obtained for this proposal indicate that these interactions are other than effects on solubility. Phenytoin's long-range side effects include changes in glucose and calcium homeostasis. Its mechanism of action in excitable cells appears to involve the drug's binding to membrane protein channels controlling cellular ion transport (specifically sodium and calcium). This binding is enhanced in depolarized cells including those in epileptic foci. The existence of similar membrane proteins involved in nutrient- ion cotransport in the leaky epithelia of the small intestine and ion transport in the tight epithelia of the large intestine suggests phenytoin binding in the GI tract. The extent of this binding will be affected by nutrient and ion transport-induced depolarization of enterocytes. Thus the presentation in the intestinal lumen of certain coadministered nutrients and ions are suspected of altering phenytoin's binding to these intestinal transport proteins resulting in drug absorption effects through a parallel pathway. Isolation of this phenomenon will be done experimentally through rat intestinal perfusion studies since this degree of isolation could most directly link the interaction to clinical significance. However, more isolated in vitro studies including intestinal ring uptake, voltage clamping, and possbily brush-border and inside-out basolateral membrane vesicles as well as isolated cell suspensions may be required to uncouple those ion trnasport processes effecting phenytoin membrane transport. In vivo dog experiments will be used to separate solubility effects from solution- membrane interactions.