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: 7119179
• 负责人: RORY P REMMEL
• 金额: $ 33.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119179
• 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(AEDs)在老年人群中的药代动力学和代谢研究很少，特别是在美国增长最快的人群中的老年人(患者)。葡萄糖醛酸化是包括拉莫三嗪、奥卡西平和丙戊酸在内的几种AEDs的主要代谢途径。在这个项目中，将用一种新的稳定同位素技术研究拉莫三嗪和丙戊酸在年轻人(18-50岁)和老年患者(65-74岁和75岁)中的药代动力学。在2-羟丙基-β-环糊精的水溶液中，将制备拉莫三嗪稳定标记同位素的创新配方。该药物的葡萄糖醛酸化反应以及苯妥英的主要氧化代谢物丙戊酸p-HPPH和奥卡西平的活性形式10-羟卡马西平将使用从老年捐赠者那里获得的预先存在的人肝微体组织库进行研究。负责这些AED和代谢物葡萄糖醛酸化的单个葡萄糖醛酸基转移酶将通过对微生物体的动力学研究和克隆表达酶的筛选来鉴定。这些研究将有助于预测药物相互作用 可能发生在AEDs之间以及AEDs和其他葡萄糖醛酸化的药物之间。单个药物的相互作用将在体外研究老年捐赠者制备的微生物体。该项目的目标是确定AED葡萄糖醛酸化是否受年龄的影响，并为主要的老年年龄组制定剂量指南：年轻人、老年人和老年人。