INTERACTIONS AFFECTING PHENYTOIN INTESTINAL

影响苯妥英肠的相互作用

• 批准号: 3476719
• 负责人: DAVID FLEISHER
• 金额: $ 8.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3476719
• 关键词: anticonvulsants; basolateral membrane; binding proteins; brush border membrane; calcium metabolism; calcium transporting ATPase; dogs; epilepsy; gastrointestinal absorption /transport; glucose transport; homeostasis; ion transport; laboratory rat; membrane channels; membrane permeability; nutrient interaction; pharmacokinetics; phenytoin

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.

这项研究的目的是确定 同时给予葡萄糖和钙会影响肠道 口服抗惊厥药苯妥英的吸收， 从解决方案。 苯妥英治疗范围窄 轻微的血液水平波动会导致严重的临床症状， 活动或有效性不足的影响 用药过量 虽然药物从溶液中吸收良好，但其 溶出不良和与联合给药物质的相互作用 在胃肠道（GI）中， 吸收 其中两种物质（葡萄糖和钙） 影响苯妥英在肠膜上的相互作用 溶液 文献中的几份报告和初步数据 这表明，这些相互作用是 除了对溶解度的影响之外。 苯妥英的长期副作用包括葡萄糖的变化， 钙稳态 它在兴奋细胞中的作用机制 似乎涉及药物与膜蛋白的结合 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增强，包括 癫痫灶中的那些。 与营养相关的类似膜蛋白的存在- 小肠渗漏上皮细胞中的离子共转运， 大肠紧密上皮细胞的离子转运表明 胃肠道中的苯妥英结合。 这种约束力的范围将 受营养和离子运输诱导的去极化影响 肠上皮细胞 因此，在肠腔中呈现 怀疑某些共同施用的营养物和离子 改变苯妥英与这些肠道转运蛋白的结合 导致通过平行途径的药物吸收效应。 这种现象的分离将通过实验来完成， 大鼠肠灌注研究，因为这种程度的隔离可以 最直接地将相互作用与临床意义联系起来。 然而，更多的孤立的体外研究，包括肠环 吸收、电压箝位、可能的刷状边界和由内向外 基底外侧膜囊泡以及分离的细胞悬液 可能需要将这些离子传输过程解耦 影响苯妥英膜转运。 犬体内实验 将被用来从溶液中分离溶解度效应- 膜相互作用