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Non-steroid anti-inflammatory drugs: Influence of extra-cellular pH on biodistribution and pharmacological effects

1978; Elsevier BV; Volume: 27; Issue: 4 Linguagem: Inglês

10.1016/0006-2952(78)90388-x

1873-2968

Kay Brune, Peter Gräf,

Sphingolipid Metabolism and Signaling

Former observations on the biodistribution of (acidic) non-steroid anti-inflammatory drugs (NSAID) prompted us to investigate whether NSAID influence cell functions to a greater extent when acting under acidic extracellular pH conditions in vitro, and, if so, whether their enhanced effects might be due to an altered biodistribution of NSAID between extracellular space and cell interior under these conditions. The following experiments were done: Firstly, the effect of NSAID on phagocytosis and antimicrobial activity of human granulocytes was measured under normal (pH 7.4) and acidic (pH 6.8) conditions. NSAID were found to be most effective under low extracellular pH conditions whilst, alkaline drugs, serving as controls, were more effective at pH 7.4. Secondly, the influence of pH changes on the distribution of an acidic and an alkaline pyrazolone derivative between buffer and erythrocytes (or erythrocyte components) was measured. Lowering of extracellular pH caused an 80 per cent increase of the cellular concentration of the acidic NSAID while it (slightly) decreased the cellular concentration of the alkaline derivative. Ion trapping together with increased binding to cellular components was found responsible for this effect. These experiments show that the acidic environment of cells may cause accumulation of (acidic) NSAID within cells and thus enhance inhibition of various cell functions. The observations reported further support our concept that biodistribution is an important factor for the effects and side effects of NSAID.