IN-VITRO INTERACTION OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON OXIDATIVE-PHOSPHORYLATION OF RAT-KIDNEY MITOCHONDRIA - RESPIRATION AND ATP SYNTHESIS

The in vitro interference of some of most important nonsteroidal anti- inflammatory drugs (NSAIDs) with the respiration of rat kidney (renal cortex) mitochondria and ATP synthesis was evaluated. Acetylsalicylic acid, diclofenac sodium, mefenamic acid, and piroxicam both uncoupled and inhibited oxidative phosphorylation in mitochondria energized with glutamate plus malate or with succinate, while dipyrone only uncouple d and paracetamol only inhibited it. The drug concentrations affecting mitochondrial respiration were in the low to middle micromolar range for diclofenac, mefenamic acid, and piroxicam, and in the low millimol ar range for acetylsalicylic acid, dipyrone, and paracetamol. The patt ern of inhibition, except for the paracetamol, was similar to that exp ressed by the respiratory chain inhibitors. NSAIDs also inhibited the rate of ATP synthesis in mitochondria energized with glutamate plus ma late, as well as the phosphorylation potential of mitochondria. The IC 50 values for rate of ATP synthesis, using 2 mM ADP, were about 0.1 mM for diclofenac sodium and mefenamic acid, 0.7 mM for piroxicam, and i n the range of 5-8 mM for acetylsalicylic acid, dipyrone, and paraceta mol. The potential for renal energetic cytotoxicity of NSAIDs is discu ssed considering their ability to interact with the oxidative phosphor ylation in rat renal cortex mitochondria. A comparison is made with th e interference of salicylate, the main metabolite of acetylsalicylic a cid, and a classical uncoupler of oxidative phosphorylation. (C) 1996 Academic Press, Inc.