Indications
Aceclofenac is primarily indicated for the alleviation of pain and inflammation associated with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. These conditions involve chronic inflammatory processes that necessitate effective management to improve patient quality of life.
Pharmacodynamics
As a non-steroidal anti-inflammatory drug (NSAID), aceclofenac functions by inhibiting both isoforms of the cyclooxygenase (COX) enzyme, essential in the inflammatory cascade. It demonstrates greater selectivity towards the COX-2 isoform (IC50 of 0.77 µM) as opposed to COX-1 (IC50 of >100 µM), which contributes to its enhanced gastric tolerance relative to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also exhibits minimal COX-2 inhibition with an IC50 value of 36 µM. Beyond inhibiting prostaglandin (PGE2) synthesis, aceclofenac reduces inflammatory cytokines, such as interleukins (IL-1β, IL-6) and tumor necrosis factors (TNF). It is also known to influence cell adhesion molecules from neutrophils and affects glycosaminoglycan synthesis, providing chondroprotective effects.
Absorption
Aceclofenac is swiftly and completely absorbed from the gastrointestinal tract when administered orally. It primarily circulates as an unchanged compound, reaching peak plasma concentrations within 1.25 to 3 hours post-ingestion. The drug effectively penetrates the synovial fluid, achieving concentrations up to 60% of plasma levels. During regular dosing, there is no significant accumulation, and both the maximum plasma concentration (Cmax) and the time to reach it (Tmax) remain consistent following single and repeated dosing.
Metabolism
The primary metabolic product of aceclofenac is 4'-hydroxyaceclofenac, while various other minor metabolites such as diclofenac, 5-hydroxyaceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac are also detected. The metabolic process is likely facilitated by the enzyme CYP2C9.
Mechanism of Action
Aceclofenac functions primarily through the inhibition of the cyclooxygenase-2 (COX-2) enzyme, which results in the downregulation of key inflammatory mediators such as prostaglandin E2 (PGE2), interleukin-1 beta (IL-1β), and tumor necrosis factor (TNF) within the arachidonic acid pathway. While the suppression of interleukin-6 (IL-6) is associated with diclofenac, a metabolite of aceclofenac, the overall reduction in inflammatory cytokines subsequently lowers the production of reactive oxygen species. Furthermore, research indicates that aceclofenac decreases the synthesis of nitric oxide in human articular chondrocytes. It also affects cellular interactions by hindering neutrophil adhesion to the endothelium, achieved by reducing the expression of L-selectin (CD62L), a molecule crucial for lymphocyte adhesion. Additionally, aceclofenac may promote the synthesis of glycosaminoglycans in osteoarthritic cartilage, potentially through its inhibition of IL-1 production and activity. The chondroprotective properties of aceclofenac are attributed to 4'-hydroxyaceclofenac, which suppresses IL-1-induced production of promatrix metalloproteinase-1 and metalloproteinase-3, thereby preventing the release of proteoglycans from chondrocytes.
