Molecular interactions of mefenamic acid with lipid bilayers and red blood cells

Abstract

O ácido mefenâmico é um anti-inflamatório não esteroidal (NSAID), também prescrito no tratamento da dor. No presente trabalho, os efeitos estruturais na membrana de eritrócitos humanos e de modelos moleculares foram investigados. Esta última foi composta em bicamadas construídas de dimiristoilfosfatidilcolina (DMPC) e dimiristoilfosfatidiletanolamina (DMPE), classes de lipídios encontrados nas porções interna e externa do eritrócito e da maioria das membranas celulares, respectivamente. Este artigo apresenta evidências de que o ácido mefenâmico interage com as membranas das células vermelhas, como segue: (i) em estudos de microscopia eletrônica de varredura (SEM) em eritrócitos humanos, foi observado que a droga induziu mudanças na forma, produzindo estomatócitos; (ii) estudos de difração de raios X mostraram que a droga interagiu com bicamadas de DMPC e efeitos de perturbação um pouco menores, em DMPE, foram detectados; (iii) medições de FT-IR mostraram que NSAID induziu a fluidização das cadeias acílicas de ambos, DMPC e DMPE; (iv) a espectroscopia de transferência de energia por ressonância Förster (FRET) indicou uma rápida intercalação do ácido mefenâmico nas cadeias hidrofóbicas do lipossoma DMPC.Mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID), also prescribed to treat pain. In the present work, the structural effects on the human erythrocyte membrane and molecular models have been investigated. The latter consisted in bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), classes of lipids found in the outer and inner moieties of the erythrocyte and most cell membranes, respectively. This report presents evidence that mefenamic acid interacts with red cell membranes as follows: (i) in scanning electron microscopy (SEM) studies on human erythrocytes it has been observed that the drug induced shape changes, forming stomatocytes; (ii) X-ray diffraction showed that the drug interacted with DMPC bilayers; somewhat lower perturbing effects on DMPE were detected; (iii) FT-IR measurements showed that NSAID induced fluidization of both DMPC and DMPE acyl chains; (iv) Förster resonance energy transfer spectroscopy (FRET) indicated a rapid intercalation of the mefenamic acid into DMPC liposome hydrophobic chains.

Unraveling the Role of Drug-Lipid Interactions in NSAIDs-Induced Cardiotoxicity

“…For instance, the fatty acid composition and the membrane fluidity of the erythrocytes of hypertensive patients was found to be disturbed in comparison with normotensive subjects [ 14 , 15 ]. Simultaneously, various NSAIDs were found to induce morphologic changes in red blood cells, including mefenamic acid, diclofenac, ibuprofen, naproxen, and aspirin [ 16 , 17 , 18 , 19 , 20 ]. In this sense, it is conceivable that NSAIDs-induced changes in biological membranes are an additional mechanism underlying the cardiotoxicity of these drugs.…”

Biophysical study of the non-steroidal anti-inflammatory drugs (NSAID) ibuprofen, naproxen and diclofenac with phosphatidylserine bilayer membranes

“…It has been suggested that NSAIDs should be tested in combination with chemotherapy and radiotherapy to potentiate the anti-tumor effect. Although most of the biological activities of NSAIDs are related with COX-dependent mechanisms, several studies have demonstrated that NSAIDs interact with membrane phospholipids in a COXindependent path that could be involved in their biological activity [16][17][18][19][20][21][22][23][24][25].…”