Hepatic to 2-amino-3-acetylamino-6-(para-fluorobenzylamino) pyridine (which has 20-30% the analgesic potential of its parent compound), para-fluorohippuric acid and a mercapturic acid metabolite, presumably formed from a glutathione adduct
Flupirtine is an aminopyridine that functions as a centrally acting non-opioidanalgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. Flupirtine is sold by Intas Pharma under the brand name Pruf in India. Like nefopam, it is unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal centrally acting analgesic. In 2010 the chemically related drug (the difference being that the pyridine group in flupirtine is replaced with a phenyl group) retigabine (INN; ezogabine [USAN]) was approved by the FDA as an anticonvulsant for the treatment of refractory partial-onset seizures in treatment-experienced patients. Retigabine also works by opening the neuronal KCNQ/Kv7 potassium channel, just like flupirtine.
Flupirtine was originally developed by Asta Medica, with the synthesis of the compound and the development of the drug described in patents from the 1970s to the 2000s.
It was approved for the treatment of pain in 1984 in Europe. However, it has never been introduced to the United States market for any indication. In 2008, Adeona Pharmaceuticals, Inc. (now called Synthetic Biologics, Inc.) obtained an option to license issued and patent pending applications relating to flupirtine’s use in the treatment of ophthalmic indications, particularly retinitis pigmentosa.
Flupirtine is used as an analgesic for acute and chronic pain, in moderate-to-severe cases. Its muscle relaxant properties make it popular for back pain and other orthopedic uses, but it is also used for migraines, in oncology, postoperative care, and gynecology.
Although some studies have reported flupirtine has no addictive properties, there was suggestion that it may possess some abuse potential and liability. There were at least two registered cases of flupirtine abuse.Drug tolerance does not develop in most cases; however, tolerance may develop in single cases.
^Narang, PK; Tourville JF; Chatterji DC; Gallelli JF (1984). "Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection". Journal of Chromatography305 (1): 135–143. doi:10.1016/S0378-4347(00)83321-6. PMID6707137.
^Methling, K; Reszka P; Lalk M; Vrana O; Scheuch E; Siegmund W; Terhaag B; Bednarski PJ (2008). "Investigation of the in Vitro Metabolism of the Analgesic Flupirtine". Drug Metabolism and Disposition37: 479–493. doi:10.1124/dmd.108.024364.
^http://www.freepatentsonline.com/5721258.html Primary and secondary neuroprotective effect of flupirtine in neurodegenerative diseases The synthesis of flupirtine and its pharmaceutically acceptable salts is described in EP 160 865 and 199 951. EP0199951 December, 1986 Process for the preparation of 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine and of 2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino) pyridine.
^http://www.faqs.org/patents/app/20090306150 CARBOXYLIC ACID SALTS OF 2-AMINO-3-CARBETHOXYAMINO-6-(4-FLUORO-BENZYLAMINO)-PYRIDINE patent 20090306150. 2009. Flupirtine is commonly used in the form of pharmaceutically acceptable acid addition salts. Commercially, flupirtine is available as its maleate addition salt under the trademark Katadolon®. There are two known polymorphs of flupirtine maleate, designated in the art as flupirtine maleate A and B. European patentEP 0 977 736 discloses pure flupirtine maleate crystalline form A and a process for its preparation. Flupirtine and mixtures of flupirtine maleate polymorphs A and B can be synthesised according to EP 0 199 951.
^Kornhuber, J.; Bleich, S.; Wiltfang, J.; Maler, M.; Parsons, C. G. (1999). "Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication". Journal of neural transmission (Vienna, Austria : 1996)106 (9–10): 857–867. doi:10.1007/s007020050206. PMID10599868.edit
^McMahon, FG; Arndt WF Jr, Newton JJ, Montgomery PA, Perhach JL. (1987). "Clinical experience with flupirtine in the U.S". Postgraduate Medical Journal63 (3): 81–85. PMID3328854.Cite uses deprecated parameter |coauthors= (help)
^Klawe, C; Maschke, M (2009). "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert opinion on pharmacotherapy10 (9): 1495–500. doi:10.1517/14656560902988528. PMID19505216.
^Dhar S, Bitting RL, Rylova SN et al. (April 2002). "Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons". Ann. Neurol.51 (4): 448–66. doi:10.1002/ana.10143. PMID11921051.CS1 maint: Explicit use of et al. (link)
^Preston, KL; Funderburk, FR; Liebson, IA; Bigelow, GE (Mar 1991). "Evaluation of the Abuse Potential of the Novel Analgesic Flupirtine Maleate". Drug and Alcohol Dependence27 (2): 101–113. doi:10.1016/0376-8716(91)90027-v. PMID2055157.|accessdate= requires |url= (help)
^Sofia, RD; Diamantis, W; Gordon, R (1987). "Abuse Potential and Physical Dependence Liability Studies with Flupirtine Maleate in Laboratory Animals". Postgraduate Medical Journal. 63 Suppl 3: 35–40. PMID3447127.|accessdate= requires |url= (help)
^Gahr, M; Freudenmann, RW; Connemann, BJ; Hiemke, C; Schönfeldt–Lecuona, C (Dec 2013). "Abuse Liability of Flupirtine Revisited: Implications of Spontaneous Reports of Adverse Drug Reactions". Journal of Clinical Pharmacology53 (12): 1328–1333. doi:10.1002/jcph.164. PMID24037995.|accessdate= requires |url= (help)