Inhibitory effect of indomethacin farnesil, a novel antiinflammatory prodrug, on carrageenin-induced inflammation in rats.
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.
Kumakura
S
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Mishima
M
M
Kobayashi
S
S
Shirota
H
H
Abe
S
S
Yamada
K
K
Tsurufuji
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005122:Exudates and Transudates / Q000378:metabolism; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007700:Kinetics; D007962:Leukocytes / Q000473:pathology; D008297:Male; D011355:Prodrugs; D051381:Rats; D011919:Rats, Inbred Strains
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D002351:Carrageenan; D015232:Dinoprostone; C060022:indomethacin farnesil; D007213:Indomethacin