ANTIEPILEPTIC DRUG METABOLISM IN ELDERLY USING STABLE ISOTOPES

使用稳定同位素的老年人抗癫痫药物代谢

• 批准号: 6349228
• 负责人: JAMES C. CLOYD
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349228
• 关键词: aging; antidepressants; blood chemistry; carbamazepine; chemical binding; clinical research; cytochrome P450; dosage; enzyme activity; epilepsy; gas chromatography mass spectrometry; glucuronosyltransferase; human old age (65+); human subject; nervous system disorder epidemiology; nursing homes; pharmacokinetics; phenytoin; stable isotope; urinalysis

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.

该项目将描述高龄如何改变苯妥英， 卡马西平药代动力学和代谢。 具体地说，这 项目将确定细胞色素P-450同工酶（CYP 2C 9， CYP 2C 18、CYP 2C 19和CYP 3A 4）负责代谢 这些药物在老年人中会减少。 完整的表征 抗癫痫药物（AED）的药代动力学和代谢需要 静脉给药和加强血液和尿液 在稳态条件下采样。 该项目将使用一个 老年患者处置研究的新方法：稳定标记 同位素和色谱/质谱法。 60岁老人 （大于或等于65岁）的男女， 三个年龄组（10岁，老年人和老年人）服用苯妥英钠将 从参与的诊所和疗养院招募。 结果 将60名老年人的结果与 十个年轻的病人 同样的方法将用于 卡马西平 小剂量稳定的苯妥英或卡马西平 将通过静脉注射标记的同位素， 将在五天内收集样本。 全部和非结合 血浆药物和代谢物浓度以及尿液药物和 将测量代谢物浓度。 绝对生物利用度， 游离分数、分布容积、消除半衰期和清除率 将计算CYP 2C 9、CYP 2C 18 CYP 2C 19和CYP 3A 4代谢途径转化为苯妥英，或 消除卡马西平。 这些结果将用于确定是否 老年人药代动力学变化的机制是由于 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 与年轻患者相比。 此外，本发明还提供了一种方法， 三个老年组之间的药代动力学变化将 通过多变量回归分析进行评估。 我们的成果将被用于 制定合理的剂量、给药频率和 监测总药物和游离药物水平。