Identification of a hydroxy metabolite of diflunisal in rat and human urine

Abstract

1. A new metabolite of diflunisal, a hydroxy derivative, has been identified in rat and human urine following administration of diflunisal. 2. This hydroxy metabolite of diflunisal is excreted in urine of both species as a polar conjugate, most likely a sulphate. 3. Attempts to isolate the polar conjugate in pure form were unsuccessful due to its rapid hydrolysis in the presence of acid, and organic solvents such as diethyl ether. Its breakdown product, however, was more stable and was isolated and purified by semi-preparative h.p.l.c. Unequivocal identification as 3-hydroxy-diflunisal (i.e. hydroxylation in position 3 of the salicylic acid ring) was accomplished by means of FAB-mass spectrometry and n.m.r. spectroscopy. 4. The contribution of this oxidative metabolic pathway to the overall elimination scheme of diflunisal is more important in rat than in man. Gunn rats excrete more of the hydroxy diflunisal conjugate in urine (20-30% of a 50 mg/kg i.v. dose of diflunisal) than Wistar rats. In healthy humans, hydroxylation of diflunisal contributes only to a small extent to the overall biotransformation of diflunisal.

Efficient biotransformation of non-steroid anti-inflammatory drugs by endophytic and epiphytic fungi from dried leaves of a medicinal plant, Plantago lanceolata L.

“…Nine of these metabolites were shown to be either mono-, or dihydroxy derivatives of the original anti-inflammatory drug molecules. The products generated by the fungi of the current study are similar to those found in the phase I metabolism of mammalsmetabolism to various hydroxylated products was shown for these pharmaceuticals (Macdonald et al, 1991;Wing Lam et al, 2007;Stülten et al, 2008;Tevell Åberg et al, 2009;Borges et al, 2010). These metabolites can be less toxic or more toxic compared to the original compounds.…”

“…So far, no fungal metabolites of DIF have been described in the literature. The compound showed peaks identical to those described in the literature (Macdonald et al, 1991;Dickinson et al, 1994). As in the case of DIC, the halogenated ring was untouched; MS (Paíga et al, 2015), most probably the isobutyl sidechain is hydroxylated.…”

The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.

“…The remaining 10-15% may be excreted in the bile and faeces or it may be excreted in the urine as the 3-hydroxy metabolite of diflunisal (i.e. hydroxylation in position 3 of the salicylic acid ring), identified recently in human urine by Macdonald et al (1989).…”