Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs-induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects.

Keywords: ATP; Biological membranes; COX; COX-2 selective inhibitors; CV; Coxibs; DPPC; GI; GUVs; LB; LOX; LUVs; Langmuir-Blodgett; MD; MLVs; Membrane model systems; NO-NSAIDs; NSAIDs; Nonsteroidal anti-inflammatory drugs; PC-NSAIDs; PG; Pharmacokinetic properties; SLB; SUVs; Therapeutic and toxic actions; Tx; adenosine triphosphate; cardiovascular; cyclooxygenase; dipalmitoylphosphatidylcholine; gastrointestinal; giant unilamellar vesicles; large unilamellar vesicles; lipoxygenase; mPGES-1; microsomal prostaglandin E synthase-1; molecular dynamics; multilamellar lipid vesicles; nitric oxide-releasing nonsteroidal anti-inflammatory drugs; nonsteroidal anti-inflammatory drugs; phosphatidylcholine-associated nonsteroidal anti-inflammatory drugs; prostaglandin; small unilamellar vesicles; supported lipid bilayers; thromboxane.