A mechanistic approach to understanding species differences in felbamate bioactivation: relevance to drug-induced idiosyncratic reactions.

In an attempt to understand the species-selective toxicity of felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM), which is thought to result from bioactivation to 2-phenylpropenal, FBM metabolism was evaluated in rats and humans. The formation of 2-phenylpropenal was monitored by the amount of its mercapturates excreted in urine. The data show a relative 5-fold increase in mercapturate excretion in patient urine as a result of differences in metabolism through P450-, esterase-, and aldehyde dehydrogenase-mediated pathways. To compensate for the significant species differences in FBM metabolism, and to produce toxic levels of 2-phenylpropenal in rat comparable to humans levels, monocarbamate felbamate (2-phenyl-1,3-propanediol monocarbamate, MCF), was administered to rats in the hopes of eliciting a toxic response. The desired result, an increase in mercapturate excretion, was not observed in MCF-treated rats due to the identification of a new FBM metabolite, 2-phenyl-1,3-propanediol monocarbamate-alpha-D-glucuronic acid (MCF-glucuronide). Formation of MCF-glucuronide is significant and represents about 80% of MCF metabolites in MCF-dosed rats, 3% of FBM metabolites in FBM-dosed rats, and about 11% of FBM metabolites in FBM patients. To overcome the protective effect of glucuronidation, uridine diphosphoglucuronosyltransferase (UGT)-deficient Gunn rats were treated with FBM and MCF, which surprisingly had no effect on the amount of MCF-glucuronide formed. Given the known UGT polymorphisms and the fact that MCF glucuronidation contributes to the elimination of a 2-phenylpropenal precursor, the correlation between poor UGT activity and an increase in mercapturates excretion was evaluated in patients. The result of the first 34 patients screened suggests that a patient with poor UGT activity is not necessarily at risk for FBM toxicity.