Effect of age on glucuronidation of antiepileptic drugs

抗癫痫药物（AED）在老年人群中的药代动力学和代谢研究很少，特别是在老年人和老年人（患者>-75）中，这是美国增长最快的人群。葡萄糖醛酸化是几种AED（包括拉莫三嗪，奥卡西平和丙戊酸）的主要代谢途径。在本项目中，将通过一种新的稳定同位素技术研究拉莫三嗪和丙戊酸在年轻成人（年龄18-50岁）和老年患者（年龄65-74岁和>-75岁）中的药代动力学。拉莫三嗪的稳定标记同位素的创新制剂将在2-羟丙基-β-环糊精的水溶液中制备。将使用从老年供体中获得的既存人肝微粒体组织库对本品以及丙戊酸（苯妥英的主要氧化代谢产物p-HPPH和奥卡西平的活性形式10-羟基卡马西平）的葡萄糖醛酸化进行研究。将通过微粒体动力学研究和克隆表达酶筛选来鉴别负责这些AED和代谢物葡萄糖醛酸化的单个葡萄糖醛酸基转移酶。这些研究将有助于预测药物相互作用， 可能发生在AED之间以及AED和其他葡萄糖醛酸化药物之间。将在老年供体制备的微粒体中体外研究个体药物相互作用。该项目的目标是确定AED葡萄糖醛酸化是否受年龄的影响，并为主要老年年龄组制定剂量指南：老年人，老年人和老年人。

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.