RELATIONSHIP BETWEEN NAPROXEN PLASMA-CONCENTRATION AND ITS ANTIINFLAMMATORY EFFECT IN EXPERIMENTAL HEPATITIS

The relationship between the plasma concentration and the anti-inflamm atory effect of naproxen (GAS 22204-53-1) after oral administration of a 6 mg . kg(-1) dose was studied in rats with galactosamine-induced a cute hepatitis and under control conditions. In control animals naprox en peak plasma levels of 35 +/- 0.4 mu g . ml(-1) were reached in 0.5 +/- 0 h. Concentration then decayed half-life being 5.2 +/- 0.4 h. AUC was 131 +/- 5 mu g . h . ml(-1) In intoxicated mts peak plasma levels of 29 +/- 0.3 mu g . ml(-1) were reached in 0.7 +/- 0.1 h, half-life was increased to 11.1 +/- 1.3 h, and the AUC reached 259 +/- 21 mu g . h . ml(-1). In control rats the protective effect of naproroxen again st carrageenan-induced inflammation increased slowly, reaching a maxim um of 38 % in 4 h. The protective effect against plasma concentration curve exhibited a clear counterclockwise hysteresis, probably due to a slow naproxen transport from the circulation to its site of action. I n animals with hepatitis, the protective effect remained quite constan t at about 40 % despite variations in plasma levels probably because t he maximal effect was reached. No clear hysteresis was observed in the effect-plasma concentration curve, suggesting that naproxen arrival t o its site of action was faster. Results show that the relationship be tween naproxen plasma concentration and its anti-inflammatory effect i s complex and therefore predictions on the pharmacological response in liver damage cannot be readily made by solely considering pharmacokin etic data.