indomethacin-farnesil and Inflammation

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biotransformation; Carrageenan; Hydrolysis; Indomethacin; Inflammation; Kinetics; Lymph; Male; Pancreatic Juice; Prodrugs; Rats; Rats, Inbred Strains; Tissue Distribution

Antiinflammatory effects of indomethacin farnesil (IMF), a novel prodrug of indomethacin, was examined after both oral and local administration. In the air pouch carrageenin-induced inflammation, an oral dose of IMF exerted dose dependent inhibitory effects on the accumulation of inflammatory exudate fluid and the migration of leukocytes into the exudate. Both the increased vascular permeability and the prostaglandin E2 levels in the exudate fluid were reduced by IMF. Significant levels of free indomethacin were detected in the pouch fluid. In spite of the inability of IMF to inhibit prostaglandin synthesis in a cell free cyclooxygenase system, IMF injected locally inhibited carrageenin paw edema, and the inhibitory effect was comparable to that of indomethacin itself. When injected locally into the paw together with carrageenin, 14C-IMF was effectively converted to its active metabolite, indomethacin. The indomethacin concentration in the paw tissue was comparable to that of indomethacin injected paws with the same molar dose of free indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Dinoprostone; Edema; Exudates and Transudates; Indomethacin; Inflammation; Kinetics; Leukocytes; Male; Prodrugs; Rats; Rats, Inbred Strains