Studies on the fate of naproxen. II. Metabolic fate in various animals and man.

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Abstract
The species differences in the metabolism of naproxen [(+)-6-methoxy-.alpha.-methyl-2-naphthaleneacetic acid, a non-steroidal antiinflammatory agent] were investigated in 6 species of animals and in man. 3H-Naproxen was orally administered to mice, rats, rabbits, guinea pigs, dogs and miniature pigs (OHMINI-875) and cold naproxen to human subjects, and their urinary and biliary (rats only) metabolites were separated and characterized by TLC gas chromatography, high-performance liquid chromatography and gas chromatography-mass spectrometry. The excretion rates as percent of dose of naproxen and its metabolites in the 24 h urine were, in a decreasing order: miniature pig, 82.5; mouse, 80.4; rat, 74.7; rabbit, 70.3; guinea pig, 48.5 and dog, 23.0%. Naproxen and its metabolites, i.e., 6-hydroxy .alpha.-methyl-2-naphthaleneacetic acid (6-DMN), naproxen glucuronide, 6-DMN glucuronide and 6-DMN sulfate, were found in the urines of all species. Urinary naproxen in the rat was only 0.2% and that in the other species of animals was 4.8-13.7% of the urinary radioactivity, while in man it was 1.3% of dose. The main urinary metabolite in rat, guinea pig, dog, mouse and rabbit was 6-DMN sulfate (87.3, 46.7, 42.9, 39.9 and 36.2% of the urinary radioactivity, respectively), while those in man and miniature pig were naproxen glucuronide (25.3% of dose) and 6-DMN (78.6% of the urinary radioactivity), respectively. The animals whose urinary metabolic profiles were the nearest to that of man were the guinea pig and mouse, while the animals that differed most from man in this regard were the rat and miniature pig.

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