Metabolic fate of indometacin farnesil, a prodrug of indomethacin: characteristic biotransformation of indometacin farnesil in rats.

1. Hydrolysis of indometacin farnesil (IMF), a farnesyl ester of indomethacin, was higher in plasma and pancreatic juice than in liver and kidney homogenates of rats. Plasma hydrolytic activity was extremely low in beagle dog, monkey and human. 2. Orally administered 14C-IMF was absorbed mainly via the throacic lymph duct and distributed into tissues such as liver, adrenal and spleen as the unchanged from; the 14C in rat plasma was present mainly as indomethacin released from IMF. 3. The concentration ratios of indomethacin in carrageenin-induced inflamed paw to blood after 14C-IMF administration were significantly greater than those after 14C-indomethacin dosing. 4. These results indicate that absorbed IMF might be transported as the unchanged drug into tissues, including the site of inflammation and then hydrolysed to indomethacin in the tissues.