Anti-inflammatory activity of anti-hyperlipidemic drug, fenofibrate, and its phase-I metabolite fenofibric acid: in silico, in vitro, and in vivo studies

Fenofibrate, an anti-hyperlipidemic drug and its phase-I biotransformed metabolite fenofibric acid, was studied for COX-1 (PDB ID: 3N8Y) and COX-2 (PDB ID: 1PXX) inhibition potentials in silico and in vitro for their effects on human recombinant COX-2 enzyme isolated from a Baculovirus expression system in sf21 cells (EC 1.14.99.1) using a conventional spectrophotometric assay. Furthermore, the compounds were also screened for their anti-inflammatory potentials in vivo using carrageenan-induced paw oedema method in Wistar rats. The test compounds fenofibric acid, fenofibrate, and the standard drug diclofenac exhibited binding energies of − 9.0, − 7.2, and − 8.0 kcal mol⁻¹, respectively, against COX-2 and − 7.2, − 7.0, and − 6.5 kcal mol⁻¹, respectively, against COX-1. In in vitro studies, both the test compounds inhibited COX-2 enzyme activity. Fenofibric acid showed an IC₅₀ value of 48 nM followed by fenofibrate (82 nM), while diclofenac showed an IC₅₀ value of 58 nM. Furthermore, under in vivo conditions in carrageenan-induced paw oedema rodent model, fenofibric acid exhibited relatively potent anti-inflammatory activity compared with fenofibrate. Hence, we conclude that fenofibric acid and fenofibrate are not only anti-hyperlipidemic but also shows potent anti-inflammatory activity, which may have an additional impact in the treatment of diabetic complications, viz., hyperlipidemia and inflammation leading to atherosclerosis.