Flunixin

Interestingly, a substance somewhat closely related to flunixin, triflocin (30), is a diuretic rather than an antiinflammatory agent. It can be prepared by nucleophilic aromatic displacement on 4-chloronicotinic acid (29) with m-trifluoromethyl-aniline.8... 

The substantial interest in the pharmacological properties of nonsteroidal antiinflammatories prompted the development of a number of pyridine derivatives with analgesic activity. Thus, treatment of the N-oxide of nicotinic acid with phosphorus trichloride followed by hydrolysis of the resulting acid chloride gives (75), a precursor to nifluminic acid (76a) (66BSF2316), flunixin (76b) (B-80MI20903) and clonixin (76c) (67NEP6603357). 

Flunixin is registered or is under development in many countries for use in horses, cattle, and swine for treatment of equine colic, musculoskeletal disorders, acute endotoxin-induced mastitis in cattle, and respiratory disease (89-91). It is administered orally or parenterally for a maximum of 5 successive days (92). Flunixin is a genotoxic but not carcinogenic compound. Its mechanism of action is believed to be via the inhibition of cycloxygenase to reduce the presence of arachidonic acid metabolites produced during inflammation (93). 

Following single daily intravenous injections of radiolabeled flunixin in cattle at the rate of 2.2 mg/kg bw for 3 consecutive days, the parent compound accounted for 50% of the extractable tissue radioactivity, composing the major residue in liver and kidney (94). Three metabolites were also present in both liver and kidney samples 4-hydroxyflunixin was present at higher levels, whereas 5-hydroxyflunixin and 2-methylhydroxyflunixin occurred at lower levels. 

These results indicated that the primary routes of metabolism of flunixin were through oxidation of the pyridine and the phenyl ring systems, and oxidation of the methyl substituent on the phenyl moiety. The mean concentrations of flunixin in the liver were 389 ppb at 12 h postdosing, 53 ppb at 24 h, 13 ppb at 48 h, and less than 8 ppb at 72 h of withdrawal. 

Following intravenous dosing of lactating cows with 2.2 mg flunixin/kg bw, residues in milk ranged from 7.3 ppb at 16 h postdosing to 1.7 ppb at 24 h postdosing (95). 

Boner PL, Liu DDW, Feely WF et al. (2003) Determination of Flunixin in Edible Bovine Tissues Using Liquid Chromatography Coupled with Tandem Mass Spectrometry. Journal of Agricultural and Food Chemistry 51 7555-7559... 

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