Felbamate Metabolism to Potentially Toxic Metabolite(s) by Human Liver Tissue In Vitro
NR Hartman1, IM Kapetanovic2, C Lu3, CDTorchin2, AP Li3, HJ Kupferberg2 and JM Strong1,
1Lab. Clin. Pharmacol., CDER, FDA; 2NINDS, NIH, Bethesda, MD, 3In Vitro Technologies, Inc., Baltimore, MD
Aplastic anemia and hepatic failure have been reported with use of the anticonvulsant drug Felbamate (FBM). The major FBM urinary metabolite identified in humans is 3-carbamoyl-2-phenylpropionic acid (CPPA) produced by oxidation of the mono-carbamoylated metabolite (MCF). Reactive intermediary metabolites during the oxidation of MCF to CPPA were proposed including an aldehyde (CMBA) which could undergo reversible cyclization to a more stable compound (CCMF) or b-elimination to yield a proposed toxic metabolite, a, b-unsaturated aldehyde (ATPAL). Our study demonstrated the metabolic conversion of MCF to CCMF and formation of the reactive metabolite ATPAL by human liver tissue including isolated hepatocytes (fresh and cryopreserved) in vitro. Hepatocyte viability, measured by the tetrazolium dye MTT, was significantly compromised when incubated with the postulated toxin, ATPAL.