Aspects of the metabolism of the peripheral vasodilator mecinarone (14C-6809 MD) in rat, dog and man.

Abstract

The major proportion of oral doses of 14C-mecinarone was excreted in the faeces by rat, dog and man, and in all species the faecal metabolites were more polar than mecinarone and the O-desmethyl reference compounds. Rat faecal extracts contained two major components each accounting for about 30-40% of the radioactivity. Dog and human faecal extracts contained some mecinarone but also three major, more polar components, two of which corresponded to the rat metabolites. Rat bile contained three major components and dog bile two components. One of the components in both bile samples was shown to be a conjugate of O-desmethyl-mecinarone. Besides mecinarone human urine contained a component corresponding to the phenol resulting from 0-demethylation in the p-methoxycinnamoyl group. The same two compounds were also detected in human plasma. The two major components in rat and dog faecal extracts gave mass spectra identical to mecinarone and the p-hydroxycinnamoyl derivative (O-desmethyl-mecinarone). It is postulated that these thermally-labile metabolites were formed by nucleophilic addition of a substituent to the alpha, beta-unsaturated ketone. It has been demonstrated in vitro that mecinarone forms a glutathione conjugate. The metabolites may be compounds of this type where the glutathione moiety has been degraded in the gastrointestinal tract.