Acemetacin and indomethacin: differential inhibition of constitutive and inducible cyclo-oxygenases in human gastric mucosa and leucocytes.
Cyclo-oxygenase, a key enzyme in prostaglandin production, is mainly in the constitutive form (COX-1) in gastric mucosa, whereas leucocytes have an inducible enzyme (COX-2). We report that indomethacin and its glycolic acid ester acemetacin have quantitatively different effects on prostanoid synthesis in these tissues. Human gastric mucosa (fresh operation specimens, cut finely and washed), and 1-1.5 x 10(6) human blood leucocytes stimulated with lipopolysaccharide (5 micrograms/ml), were incubated with acemetacin or indomethacin (0.1, 1, 10, 100 micrograms/ml). Eicosanoids in the medium were measured by radioimmunoassay (RIA). In leucocytes, acemetacin and indomethacin were more potent cyclo-oxygenase inhibitors than in the gastric mucosa, and both reduced the PGE levels to similar extents (70-98% and 72-100% respectively, n = 5). LTB4 was reduced only at 100 micrograms/ml of either drug. In gastric mucosal incubates, acemetacin was less potent than indomethacin in causing a concentration-related inhibition of PGE accumulation (19-74% vs 34-84%; n = 6, p < 0.05). Acemetacin was also less potent than indomethacin in reducing gastric 6-keto-PGF1 alpha and TXB2 (by 11-79% vs 45-72%, and 0-80% vs 29-80% respectively, p < 0.05). The finding that acemetacin is equipotent to indomethacin on leucocyte cyclo-oxygenase (inducible enzyme, COX-2) but less active on the gastric mucosa (COX-1) is consistent with an effective analgesic and anti-inflammatory activity of acemetacin coupled with better gastric tolerance than that to indomethacin.
Tavares
I A
IA
Department of Surgery, Rayne Institute, King's College School of Medicine and Dentistry, London, England.
Bennett
A
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004790:Enzyme Induction; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; C026784:acemetacin; D007213:Indomethacin