Can NO-indomethacin counteract the topical gastric toxicity induced by indomethacin interactions with phospholipid bilayers?

Author(s)

Pereira-Leite, Catarina ^{[1, 2]} ; Nunes, Claudia ^[2] ; Bozelli, Jr., Jose C. ^{[1, 3]} ; Schreier, Shirley ^[1] ; Kamma-Lorger, Christina S. ^[4] ; Cuccovia, Iolanda M. ^[1] ; Reis, Salette ^[2]

Affiliation

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo - Brazil

^[2] Univ Porto, Fac Farm, Dept Ciencias Quim, LAQV, REQUIMTE, R Jorge Viterbo Ferreira, P-4050313 Porto - Portugal

^[3] McMaster Univ, Dept Biochem & Biomed Sci, 1280 Main St West, Hamilton, ON L8S 4L8 - Canada

^[4] ALBA Synchrotron, Consorcio Construcc, Equipamiento & Explotac Lab Luz Sincro Sincrotron, Carrer Llum 2-26, Barcelona 08290 - Spain

• Document type: Journal article
• Source: COLLOIDS AND SURFACES B-BIOINTERFACES; v. 169, p. 375-383, SEP 1 2018.
• Web of Science Citations: 1

Abstract

Nitric oxide (NO)-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) have been developed to overcome the gastrointestinal and cardiovascular toxicity of NSAIDs, by chemically associating a NO-releasing moiety with commercial NSAIDs. Since increasing evidence supports that NSAIDs toxicity is related to their topical actions in membrane lipids, this work aims to evaluate the impact of adding a NO-releasing moiety to parent NSAIDs regarding their effect on lipid bilayers. Thus, the interactions of NO-indomethacin and indomethacin (parent drug) with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers were described herein at pH 3.0 and 7.4. Diverse experimental techniques were combined to characterize the partitioning and location of drugs in DMPC bilayers, and to analyze their effect on the lipid phase transition and the bilayer structure and dynamics. The partitioning of NO-indomethacin into DMPC bilayers was similar to that of charged indomethacin and smaller than that of neutral indomethacin. Both drugs were found to insert the DMPC bilayer and the membrane location of indomethacin was pH-dependent. NO-indomethacin and indomethacin induced a decrease of the main phase transition temperature of DMPC. The effect of these drugs on the bilayer structure and dynamics was dependent on diverse factors, namely drug ionization state, drug:lipid molar ratio, temperature and lipid phase. It is noteworthy that NO-indomethacin induced more pronounced alterations in the biophysical properties of DMPC bilayers than indomethacin, considering equivalent membrane concentrations. Such modifications may have in vivo implications, particularly in the gastric mucosa, where NO-NSAIDs-induced changes in the protective properties of phospholipid layers may contribute to the occurrence of adverse effects. (AU)

• FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Research Projects - Thematic Grants