Metabolism of retigabine (D-23129), a novel anticonvulsant

Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic ac id ethyl ester) is a potent anticonvulsant ina variety of animal models. Ra ts metabolized [C-14]retigabine mainly through glucuronidation and acetylat ion reactions. Glucuronides were detected in incubates with liver microsome s or slices, in plasma, and in bile and feces but were absent in urine (0-2 4 h) that contained about 2% of the dose as retigabine and approximately 29 % of the dose in > 20 metabolites, which are derived mainly from acetylatio n reactions. About 67% of the radioactivity was excreted into feces, approx imately 10% of the dose as glucuronide, The metabolite pattern in the urine (0-24 h) of dogs was comparatively simple in that retigabine (13%), retiga bine-N-glucuronide (5%), and retigabine-N-glucoside (1%) were present. In t he same 24-h interval, about 39% of unchanged retigabine was excreted into feces. Plasma profiling and spectroscopic analysis (liquid chromatography w ith tandem mass spectrometry NMR) of two isolated urinary metabolites obtai ned after single oral dosing of 600 mg retigabine in healthy volunteers ind icated that both acetylation and glucuronidation are major metabolic pathwa ys of retigabine in humans, We found that in vitro assays with liver slices from rat and humans reveal the major circulating metabolites in vivo.