The metabolism and idiosyncratic reactions of the anti-epileptic drug felbamate

In 1993, felbamate gained approval as an anti-epileptic drug. Shortly thereafter, felbamate therapy became associated with idiosyncratic hepatotoxicity and aplastic anemia. Our laboratory proposed that 3-carbamoyl-2-phenylpropionaldehyde, an unobserved intermediate in the conversion of the known metabolite, 2-phenyl-1,3-propandiol monocarbamate to the corresponding carboxylic acid, may be central to the observed toxicities. If formed, the aldehyde intermediate could undergo β-elimination to afford the highly reactive α,β-unsaturated aldehyde, 2-phenylpropenal. In fact, processed glutathione adducts of 2-phenylpropenal have been identified in felbamate patient urine.; We hypothesize that felbamate toxicities occur in glutathione-depleted patients producing surplus 2-phenylpropenal, which reacts with endogenous proteins and elicits immune-mediated toxicity and that 2-phenylpropenal reacts at the site of formation. Therefore, felbamate bioactivation in the liver could explain the hepatotoxicity but is unlikely to explain the anemia. We further propose that 3-carbamoyl-2-phenylpropionaldhyde cyclization to the oxazolidine, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, represents a latent form of 2-phenylpropenal capable of travelling to distal sites from the liver. The oxazolidine exhibits a half-life of 4.6 hours under in vitro physiological conditions, demonstrates a GI₅₀ of 13 μM on cultured cells and has been identified in felbamate patient urine.; Additional in vitro studies characterized the role of Glutathione-S-Transferases in the detoxification of 2-phenylpropenal. The data show that 2-phenylpropenal is a substrate for GSTM1-1, GSTP1-1 and GSTA1-1, with an apparent k_cat/K_m for GSTM1-1 = 0.275 ± 0.035 μM−1·sec−1, GSTP1-1 = 0.164 ± 0.005 μM−1·sec−1 and GSTA1-1 = 0.042 ± 0.005 μM−1·sec −1. Inhibition studies demonstrate that 2-phenylpropenal reversibly inhibits GSTP1-1 and irreversibly inhibits GSTM1-1.; In vivo work focused on the development of a felbamate animal toxicity model and expansion of the “at-risk” patient urine metabolite assay. Quantification of excreted metabolites from rats gavaged with either felbamate or 2-phenyl-1,3-propanediol monocarbamate revealed that rats demonstrate a protective felbamate metabolism, generating markedly less 2-phenylpropenal than humans. Continued patient urine metabolite monitoring has evaluated over 1000 felbamate patients and has identified one patient who developed neutropenia.; Taken together, the studies regarding felbamate metabolism and idiosyncratic reactions all support 2-phenylpropenal as the reactive metabolite mediating the observed toxicities. This mechanistic understanding has led to the development of fluorinated felbamate analogues thought to retain anti-seizure activity without the toxicity.