Selective inhibition of cyclooxygenase‐2 by enflicoxib, its enantiomers and its main metabolites in vitro in canine blood

Abstract

Enflicoxib is approved for the treatment of pain and inflammation in canine osteoarthritis. The objective of this work was to assess the mechanistic basis of enflicoxib therapy investigating the COX inhibitory activity of enflicoxib (racemate), its enantiomers and its main metabolites using the canine whole blood assay. The (R)‐(+)‐Enflicoxib enantiomer and metabolite M8 (hydroxylated pyrazoline) did not induce significant COX inhibition. Enflicoxib and its (S)‐(‐)‐Enflicoxib enantiomer inhibited COX‐1 and COX‐2 with variable degree of preferential isoform inhibition, but no significant therapeutic effect is anticipated in vivo. The pyrazol metabolite showed the highest COX‐2 inhibition and was the most selective (IC50 COX‐1/ COX‐2 ratio: 19.45). As the pyrazol metabolite shows saturable binding to red blood cells, its in vivo concentrations in plasma are lower than in whole blood. Accordingly, when applying the red blood cell partitioning, the respective IC50 and IC80 for COX‐2 inhibition decreased from 2.8 µM (1129 ng/ml) and 13.4 µM (5404 ng/ml) to 0.2 µM (80.7 ng/ml) and 1.2 µM (484 ng/ml) and the selectivity ratio increased to close to 55. The corrected pyrazol metabolite IC50 and IC80 are well within the plasma levels described in treated dogs.

Enflicoxib for canine osteoarthritis: A randomized, blind, multicentre, non-inferiority clinical trial compared to mavacoxib

“…The main finding is that enflicoxib has a rapid onset of action and equivalent efficacy (statistically noninferior) and similar safety profile compared to mavacoxib, under their recommended posology. These results considered in context with the analgesic and anti-inflammatory activities of enflicoxib [ 35 ], and the inherent inflammatory component of OA, support its use for the treatment of pain and inflammation associated with OA in dogs. The relative efficacy of enflicoxib was higher than mavacoxib in most assessments and superiority over placebo was demonstrated for enflicoxib at more time points.…”

“…Enflicoxib, is a new selective COX-2 inhibitor with long-lasting activity in dogs that has recently been registered in Europe for the treatment of pain and inflammation associated with OA in dogs [33]. Enflicoxib efficacy is achieved through its active metabolite which, after repeated weekly administrations, achieves blood levels that remain stable within its therapeutic window [34][35][36].…”

Investigating Cox-2 and EGFR as Biomarkers in Canine Oral Squamous Cell Carcinoma: Implications for Diagnosis and Therapy

“…Piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), has proven beneficial in treating OSCC in dogs. Other potential options, some already licensed for managing pain and inflammation in canines, include mavacoxib [60,61], celecoxib, firocoxib, and enflicoxib [62], among others. However, it is crucial to carefully consider various factors, like the specific subtype of carcinoma, the exact nature and dose of the COX-2 inhibitor, the stage of the tumor, and the effectiveness and practicality of combining these inhibitors with other treatments [63] EGFR is a cell surface tyrosine kinase fundamental in cell proliferation, angiogenesis, and metastasis-a factor in tumor growth [26,64].…”