Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Leite, CP (Author) Other; Jamal, SK (Author) Other; Almeida, JP (Author) Other; Coutinho, A (Author) Other; Prieto, M (Author) Other; Cuccovia, IM (Author) Other; Nunes, C (Author) Other; Salette Reis (Author) FFUP

Journal

Title: Molecular Pharmacology

Vol. 97

Pages: 295-303

ISSN: 0026-895X

Publisher: American Society for Pharmacology and Experimental Therapeutics

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 7 Citations

Other information

Authenticus ID: P-00R-S97

DOI: 10.1124/mol.119.118299

Abstract (EN): The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dinnyristoyl-snglycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9