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.
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