Effect of age on glucuronidation of antiepileptic drugs

年龄对抗癫痫药物葡萄糖醛酸化的影响

• 批准号: 6666465
• 负责人: RORY P REMMEL
• 金额: $ 29.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666465
• 关键词: age difference; anticonvulsants; carbamazepine; drug interactions; drug metabolism; enzyme activity; enzyme induction /repression; epilepsy; glucuronides; glucuronosyltransferase; human middle age (35-64); human old age (65+); human subject; human tissue; patient oriented research; pharmacokinetics; phenytoin; stable isotope; tissue resource /registry; valproate; young adult human (21-34)

The pharmacokinetics and metabolism of antiepileptic drugs (AEDs) in the eldedy population is poorly studied, particularly in the old and old-old (patients >-75), that comprise the fastest growing population group in the U.S. Glucuronidation is a major metabolic pathway for several AEDs including lamotrigine, oxcarbazepine, and valproic acid. In this project, the pharmacokinetics of lamotrigine and valproic acid will be studied in younger adults (ages 18-50) and elderly patients (ages 65-74 and >-75) by a novel stableisotope technique. An innovative formulation of stable-labeled isotope of lamotrigine will be prepared in solutions of 2-hydroxypropyl-beta-cyclodextrin in water. Studies on the glucuronidation of this drug as well as valproic acid, the major oxidative metabolite of phenytoin, p-HPPH and the active form of oxcarbazepine, 10-hydroxy carbamazepine, will be conducted with a pre-existing human liver microsomal tissue bank that has been obtained from elderly donors. The individual glucuronosyltransferase enzymes responsible for the glucuronidation of these AEDs and metabolites will be identified by kinetic studies in microsomes and screening with cloned, expressed enzymes. These studies will be done to help predict drug interactions that may occur between AEDs and between AEDs and other drugs that are glucuronidated. Individual drug interactions will be studied in vitro in microsomes prepared from elderly donors. The goal of this project is to determine if AED glucuronidation is affected by age and to develop dosing guidelines for the major elderly age groups: the young-old, the old, and the old-old.

抗癫痫药物（aed）在老年人群中的药代动力学和代谢研究甚少，特别是在老年和老年（患者bb0 -75）中，这是美国增长最快的人群群体。葡萄糖醛酸化是几种aed的主要代谢途径，包括拉莫三嗪、奥卡西平和丙戊酸。在这个项目中，拉莫三嗪和丙戊酸的药代动力学将通过一种新的稳定同位素技术研究年轻人（18-50岁）和老年患者（65-74岁和60 -75岁）。在2-羟丙基- β -环糊精水溶液中制备拉莫三嗪稳定标记同位素的创新配方。该药物以及苯妥英的主要氧化代谢物丙戊酸（p-HPPH）和活性形式奥卡西平（10-羟基卡马西平）的葡萄糖醛酸化研究将在从老年供体获得的已有人肝微粒体组织库中进行。负责这些aed和代谢物糖醛酸化的单个葡萄糖醛酸转移酶将通过微粒体动力学研究和克隆表达酶的筛选来确定。这些研究将有助于预测药物相互作用