Etofenamate

Etofenamate is a flufenamic acid derivative, which is readily transported through the skin and concentrated in inflamed tissue, where it exerts anti-inflammatory and analgesic effects by inhibiting the release of histamine, lysosomal enzymes and prostaglandin.

In vitro studies have clearly shown that etofenamate inhibits both the lipoxygenase pathway and the cyclooxygenase pathway of arachidonic acid metabolism. The IC₅₀ is 1.2 × 10⁵ M for inhibition of leukotriene B₄ biosynthesis in polymorphonuclear leucocytes and 2.8 × 10⁷ M for inhibition of PGE₂ release from macrophages. These values show that etofenamate has anti-inflammatory/analgesic activity.

In human studies plasma levels after a single topical application of gel were found to be low. Levels were similar in patients with impaired kidney function. Levels are broadly independent of kidney function.

In long term study (20 or 40g gel/week for 10-36 weeks) plasma levels of up to 184 microg/1 (40g dose) in serum and dose-proportional levels up to 170 microg/1 in the synovial fluid of the knee were found.

Etofenamate, like other xenobiotics, is metabolised by the liver by oxidation and conjugation. The only active metabolite is flufenamic acid. All other degradation compounds are inactive. A change in the metabolism of etofenamate in patients with pre-existing liver damage is very unlikely because of considerable excess capacity for two main metabolisation pathways: oxidation and conjugation.

If drug metabolism were slowed, elevation and prolongation of the activity would be conceivable. The etofenamate plasma level found in these patients however are in roughly the same region as those of rheumatic patients without liver disease.

Etofenamate is excreted renally and faecally in the form of its metabolites (hydroxylations, ether cleavage, ester cleavage) and their conjugates.

Renal function has been shown not to limit etofenamate elimination during cutaneous application. In studies even in the most severe forms of renal insufficiency there were no signs of active ingredient accumulation.

Animal studies have shown no evidence of an embryotoxic or carcinogenic effect. In vitro and in vivo studies of the induction of gene and chromosome mutations were negative. A mutagenic effect appears to be adequately ruled out.