ANTIEPILEPTIC DRUG METABOLISM IN ELDERLY USING STABLE ISOTOPES

该项目将表征高龄如何改变苯妥英钠和 卡马西平的药代动力学和代谢。具体地说，这 该项目将确定细胞色素P-450同工酶(CYP2C9， C18、C19和CYP3A4)负责代谢 这些药物在老年人中会减少。完整地描述 抗癫痫药物(AED)的药代动力学和代谢需要 静脉给药和密集的血和尿 稳态条件下的采样。此项目将使用 老年患者倾向性研究的新方法：稳定标记 同位素和色谱/质量分光光度法。六十位老人 (大于或等于65岁)男女分布在 服用苯妥英遗嘱的三个年龄段(年轻、老年和老年) 从参与的诊所和疗养院招募。结果是 将来自60名老年人的结果与从 十个更年轻的病人。同样的方法将用于 卡马西平。小剂量稳定的苯妥英钠或卡马西平 标记的同位素将被静脉注射，血液和尿液 样本将在五天内采集。总计和未绑定 血浆药物和代谢物浓度和尿药浓度 将测量代谢物浓度。绝对生物利用度， 自由分数、分布体积、消除半衰期和间隙 将与CYP2C9、CYP2C18、 对苯妥英钠和苯妥英的代谢途径 卡马西平消除。这些结果将被用来确定 老年人药代动力学变化的机制(S)是合理的 引起吸收、蛋白质结合或酶活性的改变。 在老年患者中获得的药代动力学参数将是 与来自年轻患者的患者相比。此外, 三个老年组的药代动力学变化将是 采用多元回归分析进行评估。我们的研究结果将被用于 制定合理的剂量、给药频率和 监测药物总量和免费药物水平。

This project will characterize how advance age alters phenytoin and carbamazepine pharmacokinetics and metabolism. Specifically, this project will determine if the cytochrome P-450 isoenzymes (CYP2C9, CYP2C18, CYP2C19, and CYP3A4) responsible for metabolism of these drugs decline in the elderly. Complete characterization of antiepileptic drug (AED) pharmacokinetics and metabolism requires intravenous drug administration and intensive blood and urine sampling under steady-state conditions. This project will use an approach new to disposition studies in elderly patients: stable-labelled isotopes and chromatographic/mass spectrophotometry. Sixty elderly (greater than or equal to 65 years) men and women distributed among three age groups (young-old, old, and old-old) taking phenytoin will be recruited from participating clinics and nursing homes. The results from the sixty elderly will be compared to the results obtained from ten younger patients. The same approach will be used for carbamazepine. A small dose of stable phenytoin or carbamazepine labelled isotope will be administered intravenously and blood and urine samples will be collected over five days. Both total and unbound plasma drug and metabolite concentrations and urine drug and metabolite concentrations will be measured. Absolute bioavailability, free fraction, distribution volume, elimination half-life, and clearance will be calculated as will the contributions of CYP2C9, CYP2C18, CYP2C19, and CYP3A4 metabolic pathways to phenytoin or carbamazepine elimination. These results will be used to determine if the mechanism (s) for pharmacokinetic changes in the elderly are due to alterations in absorption, protein binding, or enzyme activity. Pharmacokinetic parameters obtained in elderly patients will be compared to those from younger patients. In addition, pharmacokinetic changes among the three elderly groups will be assessed by multivariant, regression analysis. Our results will be used to develop rational guidelines for dosage, dosing frequency, and monitoring of total and free drug levels.