Relationship between selective COX-2 inhibition and tissue selectivity of prostaglandin biosynthesis inhibition of zaltoprofen

Abstract

The tissue selectivity of zaltoprofen (ZP) and other non-steroidal anti-inflammatory drugs (NSAIDs), against prostaglandin (PG) biosynthesis on inflammatory site and stomach was investigated from the viewpoint of eyclooxygenase (COX) enzyme, anti-carrageenin-induced edema and ulcerogenic activity. All the drugs tested inhibited COX-1 and COX-2 activities using the refined enzymes in the concentration-dependent manner. The selectivity ratio of CO-1/CG-2 inhibition was the order that ZP (6.56) >etodolac (EL, 3.93) >diclofenac sodium (DF, 1.96) >loxoprofen (SRS-trans-alcohol form) (1.90) >indomethacin (IM, 0.16) . Selectivity for COX-2 of ZP was superior to those of other NSAIDs. The inhibitory effects of ZP, loxoprofen sodium (LP), EL and IM on the PGE2 content in the carrageenin-air pouch and the PGE2 release from the gastric ucosa of the same rat were determined. At the doses of NSAIDs which inhibited the PGE2 biosynthesis at the same degree in the carrageenin-air pouch, ZP hardly inhibited the PGE2 release from the gastric mucosa. EL and LP inhibited the PGE2 biosynthesis at the same degree between inflammatory site and gastric mucosa. On the other hand, IM markedly inhibited the PGE2 release. All NSAIDs tested inhibited the carrageenin-induced edema in the dose-dependent manner, ED50 values of ZP, EL, LP, DF and IM were 2.4, 13.8, 1.9, 6.4 and 3.7 mg/kg, p.o., respectively. On the other hand, ulcerogenic activity (UD50 value) of ZP, EL, LP, DF and INI were 45.3, 12.5, 5.9, 4.1 and 3.3 mg/kg, p.o., respectively. The good correlation between UD50 values and the inhibitory activity of the PG release from the gastric mucosa of NSAIDs was noted.From these results, it was found that the inhibitory activity of NSAIDs on the PGE2 release in the stomach correlated well with the selectivity ratio of COX-1/COX-2 inhibition using enzymes and ulcerogenic activity. So, it was suggested that the selectivities for COX-2 of NSAIDs are associated with anti-inflammatory effects and ulcerogenic activity. Also, it was found that ZP has more selectivity for COX-2 and the PG biosynthesis in the inflammatory site compared with other NSAIDs, which were used in the present study. These properties of ZP were seemed to be contributed to the lower ulcerogenic activity on clinical uses.