Species differences in the disposition and metabolism of 6,11-dihydro-11-oxodibenz[be]oxepin-2-acetic acid (isoxepac) in rat, rabbit, dog, rhesus monkey, and man

Abstract

The disposition and metabolism of 6,11-dihydro-11-oxodibenz[be]oxepin-2-acetic acid (isoxepac), a new nonsteroidal anti-inflammatory agent, has been studied in rat, rabbit, dog, rhesus monkey, and man. Animals were given single oral or parenteral doses of 5 or 50 mg/kg; man received approximately 3 mg/kg orally. Fecal excretion of radioactivity occurred in the rat (26--37%) and dog (33--49%), whereas in the other species elimination was mainly urinary (less than 83%). Biliary excretion accounted for 18--52% of the dose in the rat and dog. Enterohepatic circulation was demonstrated in both species. Plasma of all species was found to contain mainly unchanged isoxepac. The compound was rapidly eliminated from plasma of dog, rhesus monkey and man, but was more slowly eliminated in rat and rabbit. In the rabbit and dog the principal metabolites were the glycine and taurine conjugates of isoxepac, respectively, whereas in the rhesus monkey and man, isoxepac was excreted unchanged or as the glucuronide.