Abstract
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.
Footnotes
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Send reprint requests to: Dr. Roland Hempel, Corporate Research & Development, ASTA Medical Group, Biochemistry Dresden, Arzneimittelwerk Dresden GmbH, Meissner Str. 191, D-01445 Radebeul, Germany. E-mail:Dr-Roland.Hempel{at}astamedica.de
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This work was supported by the Sächsisches Ministerium für Arbeit und Wirtschaft (project number 1791).
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1 Introduced on the market by ASTA Medica AG, Frankfurt/Main, Germany; trade name: Katadolon.
- Abbreviations used are::
- CID
- collision induced dissociation
- DMSO
- dimethyl sulfoxide
- HPLC
- high-performance liquid chromatography
- MS
- mass spectroscopy
- LC
- liquid chromatography
- UDPGA
- uridine 5′-diphosphoglucuronic acid
- SPE
- solid phase extraction
- SPHPLC
- semipreparative chromatography
- A/D
- adsorption/desorption
- ESI-MS
- electrospray mass spectroscopy
- TSP-MS
- thermospray mass spectroscopy
- NMR
- nuclear magnetic resonance
- Received July 22, 1998.
- Accepted January 26, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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