INTERACTIONS AFFECTING PHENYTOIN INTESTINAL

拟议研究的目标是确定 联合应用葡萄糖和钙对肠道的影响 口服抗惊厥药苯妥英钠的吸收， 从解决方案。苯妥英的治疗范围很窄 轻微的血液水平波动会导致戏剧性的临床 对活动不足或有效的影响 服药过量。虽然这种药物从溶液中吸收良好，但它的 与共给药物质的溶解和相互作用较差 在胃肠道(GI)中会显著影响其 吸收。其中两种物质(葡萄糖和钙)出现了 苯妥英对肠膜相互作用的影响 解决方案。文献和初步数据中的几个报告 为这一提议获得的结果表明，这些相互作用是 除了对溶解度的影响外。 苯妥英的长期副作用包括血糖和 钙稳态。其在兴奋性细胞中的作用机制 似乎与药物与膜蛋白的结合有关 控制细胞离子转运的通道(特别是钠和 钙)。这种结合在去极化细胞中得到增强，包括 那些位于癫痫灶的人。 与营养素有关的类似膜蛋白的存在 小肠和小肠渗漏上皮细胞离子共转运 大肠致密上皮细胞的离子转运提示 苯妥英在胃肠道中的结合。这种约束力的程度将 受营养物质和离子传输引起的去极化的影响 肠上皮细胞。因此，在肠腔内呈现 某些共同管理的营养素和离子被怀疑 改变苯妥英钠与这些肠道转运蛋白的结合 从而通过平行途径产生药物吸收效应。 这种现象的隔离将通过实验来完成 大鼠肠道灌注研究，因为这种程度的隔离可以 最直接的联系是这种相互作用与临床意义。 然而，包括肠环在内的更多孤立的体外研究 吸收、电压钳位以及可能的刷边和由内向外 基侧膜囊泡以及分离的细胞悬液 可能需要对这些离子传输过程进行解耦 影响苯妥英膜转运。犬活体实验 将用于将溶解度效应从溶液中分离出来- 膜相互作用。

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.