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.

该项目将表征随着年龄的增长的变化和 卡马西平药代动力学和代谢。 具体来说，这是 项目将确定细胞色素P-450同工酶是否（CYP2C9， CYP2C18，CYP2C19和CYP3A4）负责代谢 这些药物在老年人中下降。 完整的表征 抗癫痫药（AED）药代动力学和代谢需要 静脉药物管理和强化血液和尿液 在稳态条件下进行采样。 这个项目将使用 在老年患者中进行性格研究的新方法：稳定标记 同位素和色谱/质量分光光度法。 六十老人 （大于或等于65岁）男人和女人分布在 三个年龄段（年龄较大，老年和老年）服用苯托因将 可以从参与诊所和疗养院招募。 结果 将六十老人与从 十名年轻患者。 同样的方法将用于 卡马西平。 一小剂量的稳定苯妥特或卡马西平 标记的同位素将静脉注射和血液和尿液 样品将在五天内收集。 总和没有 血浆药物和代谢物浓度和尿液药物以及 将测量代谢物浓度。 绝对生物利用度， 自由分数，分配量，消除半衰期和清理 将计算为CYP2C9，CYP2C18的贡献， CYP2C19和CYP3A4代谢途径或苯妥英钠的代谢途径 卡马西平消除。 这些结果将用于确定是否 老年人的药代动力学变化的机制应得 对吸收，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 与年轻患者的患者相比。 此外， 三个老年人组的药代动力学变化将是 通过多变量回归分析进行评估。 我们的结果将被使用 制定剂量，给药频率和 监测总药物水平和游离药物水平。