Metabolism of retigabine (D-23129), a novel anticonvulsant.
Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) is a potent anticonvulsant in a variety of animal models. Rats metabolized [14C]retigabine mainly through glucuronidation and acetylation reactions. Glucuronides were detected in incubates with liver microsomes or slices, in plasma, and in bile and feces but were absent in urine (0-24 h) that contained about 2% of the dose as retigabine and approximately 29% of the dose in > 20 metabolites, which are derived mainly from acetylation reactions. About 67% of the radioactivity was excreted into feces, approximately 10% of the dose as glucuronide. The metabolite pattern in the urine (0-24 h) of dogs was comparatively simple in that retigabine (13%), retigabine-N-glucuronide (5%), and retigabine-N-glucoside (1%) were present. In the same 24-h interval, about 39% of unchanged retigabine was excreted into feces. Plasma profiling and spectroscopic analysis (liquid chromatography with tandem mass spectrometry NMR) of two isolated urinary metabolites obtained after single oral dosing of 600 mg retigabine in healthy volunteers indicated that both acetylation and glucuronidation are major metabolic pathways of retigabine in humans. We found that in vitro assays with liver slices from rat and humans reveal the major circulating metabolites in vivo.
Hempel
R
R
Corporate Research & Development ASTA Medica Group, Radebeul, Germany. Dr_Roland_Hempel@astamedica.de
Schupke
H
H
McNeilly
P J
PJ
Heinecke
K
K
Kronbach
C
C
Grunwald
C
C
Zimmermann
G
G
Griesinger
C
C
Engel
J
J
Kronbach
T
T
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D002219:Carbamates / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010655:Phenylenediamines / Q000378:metabolism*; D011874:Radiometry; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002219:Carbamates; D002250:Carbon Radioisotopes; D005965:Glucuronates; D010655:Phenylenediamines; C101866:ezogabine