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Drug Metabolism and Disposition Fast Forward
First published on December 12, 2008; DOI: 10.1124/dmd.108.024364

0090-9556/09/3703-479-493$20.00
DMD 37:479-493, 2009

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Investigation of the in Vitro Metabolism of the Analgesic Flupirtine

Karen Methling, Przyemslaw Reszka, Michael Lalk, Oldrich Vrana, Eberhard Scheuch, Werner Siegmund, Bernd Terhaag, and Patrick J. Bednarski

Institutes of Pharmacy (K.M., P.R., M.L., P.J.B.) and Pharmacology (E.S., W.S.), University of Greifswald, Greifswald, Germany; Institute of Biophysics, Academy of Sciences of the Czech Republic, Bruno, Czech Republic (O.V.); and AWD.pharma GmbH & Co. KG, Dresden, Germany (B.T.)

The in vitro metabolism of flupirtine, ethyl-N-[2-amino-6-(4-fluorophenylmethyl-amino)pyridine-3-yl]carbamate, a centrally acting analgesic with muscle tone-reducing activity, was studied. Two flupirtine metabolites were already known: the N-acetylated analog D13223 [GenBank] and 4-fluorohippuric acid. The structure of flupirtine suggested that redox chemistry may play a role in metabolism, and cyclic voltammetry studies showed that the drug undergoes facile and irreversible redox reactions. Thus, oxidative metabolism was investigated first. With CYP3A1-induced rat liver microsomes an 18% turnover of flupirtine and a 20 to 25% turnover of D13223 [GenBank] took place over 30 min, but less than 5% turnover of flupirtine was observed with all human liver microsomal preparations tested, evidence that cytochrome P450 does not contribute appreciably to the metabolism in humans. Likewise, no involvement of human monoamine oxidase (isoforms A and B) was found for either flupirtine or D13223. [GenBank] In contrast, flupirtine was an excellent substrate for both human myeloperoxidase and horse radish peroxidase (HRP). These enzymes produced detectable amounts of oxidation products. Incubations of flupirtine with HRP produced an oxidation product that could be trapped with glutathione, the resulting glutathione conjugate was characterized by mass spectrometry and NMR. Metabolism of D13223 [GenBank] by both peroxidases was also observed but to a much lesser extent. Porcine liver esterases cleave the carbamate group of flupirtine, and both human N-acetyltransferases 1 and 2 acetylated the hydrolysis product, presumably descarboethoxyflupirtine, with nearly equal efficiencies to yield D13223. [GenBank] Incubations of human liver microsomes with flupirtine or the metabolite D13223 [GenBank] together with UDP-glucuronic acid gave two isomeric N-glucuronides in both cases.

Address correspondence to: Dr. Patrick J. Bednarski, Institut für Pharmazie, Universität Greifswald, 17487 Greifswald, Germany. E-mail: bednarsk{at}uni-greifswald.de






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