How Nsaids Affect Lipid Monolayer and Bilayer Properties

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis by blocking cyclooxygenase and influence gramicidin channel lifetimes in planar lipid bilayers. In the past we studied how the NSAIDs salicylic acid, acetylsalicylic acid, acetaminophen, ibuprofen and diclofenac influenced the pressure-area curve in the aqueous subphase on dipalmitoyl-PC pressure-area curves at modestly supratheraputic dosages (1 mM concentrations in the subphase). We observed consistent changes that imply these NSAIDs interact strongly with the lipid head groups of monolayers. Here we report subsequent findings using umbrella sampling molecular dynamics. Each titratable NSAID was simulated, both protonated and unprotonated, with DPPC bilayers. The neutral NSAIDs have free energy wells as deep as −10 kcal/mol in the headgroup region, whereas charged molecules were uniformly repulsed from the bilayer. These findings call for further experiments on the pH dependency of drug-bilayer interactions and suggest that neutral NSAIDs, including protonated aspirin in the low pH chyme of the stomach, interact with cell membranes and could cause adverse side effects.