DIFFERENTIAL INHIBITION OF CYCLOOXYGENASES-1 AND CYCLOOXYGENASES-2 BYMELOXICAM AND ITS 4'-ISOMER

Objective and Design: Two structurally related compounds, meloxicam (M el) and its structural 4'-isomer (4'-Mel), were compared to examine th e role of a slightly different chemical structure on cyclooxygenase (C OX) selectivity in in vitro and in vivo experimental models. Material or Subjects: In vitro studies were performed using human whole blood o btained from healthy volunteers, in vivo studies were performed in rat s. Treatment: A concentration-response curve was obtained in the whole blood assay for Mel, 4'-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either pros laglandin E-2 (PGE(2)) or thromboxane B-2 (TxB(2)). Similarly, a dose- response curve was obtained for Mel, 4'-Mel and piroxicam when measuri ng in vivo prostaglandin production, anti-inflammatory activity and ga stric tolerance to determine the dose resulting in a 50% reduction of the each parameter. Methods: COX selectivity was investigated in vitro using a human whole blood assay. PGE(2) synthesis in vivo was measure d in inflammatory exudate, in the stomach and kidneys of rats. Anti-in flammatory effects were measured in an adjuvant arthritis model and ga stric tolerance was tested in an ulcerogenicity model in vivo in rats. Results: In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4'-Mel. In infl ammatory exudate in rats, Mel and 4'-Mel inhibited PGE(2) synthesis to a similar extent, ID50 values similar to 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4'-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0. 2 mg/kg for Mel and 4'-Mel, respectively, in the rat adjuvant arthriti s model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4'-Mel. Conclusions: These data demonstrate chat the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different prof iles in vivo suggesting different therapeutic potential.