Evaluation of Felbamate and Other Antiepileptic Drug Toxicity Potential Based on Hepatic Protein Covalent Binding and Gene Expression

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• 作者：Angelique M. Leone ; L. M. Kao ; Michael K. McMillian ; Alex Y. Nie ; James B. Parker ; Michael F. Kelley ; Etsuko Usuki ; Andrew Parkinson ; Peter G. Lord ; Mark D. Johnson
• 刊名：Chemical Research in Toxicology
• 出版年：2007
• 出版时间：April 2007
• 年：2007
• 卷：20
• 期：4
• 页码：600 - 608
• 全文大小：307K
• 年卷期：v.20,no.4(April 2007)
• ISSN：1520-5010

文摘

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species suchas rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncraticreactions account for over half of toxicity-related drug failures in the marketplace, and improving thepreclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceuticalindustry. The formation of reactive metabolites is common among most drugs associated with idiosyncraticdrug reactions and may cause deleterious effects through covalent binding and/or oxidative stress. In thepresent study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine,phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expressionresponses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effectson covalent binding parameters, felbamate produced robust effects on a previously established oxidativestress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophenare known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteinsin vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproicacid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levelsin vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression wereobserved after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minoreffects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection offelbamate based on gene expression results in rat liver as having potential oxidative stressor/reactivemetabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity.Together, measurements of gene expression along with covalent binding should improve the safetyassessment of candidate drugs.