In vitro assessment of NSAIDs-membrane interactions: significance for pharmacological actions.

PURPOSE: To study interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and membrane mimetic models.
METHODS: The interactions of indomethacin and nimesulide with liposomes of dipalmitoylphosphatidylcholine (DPPC) at two physiological pH conditions (pH 7.4 and 5.0) were investigated by time-resolved and steady-state fluorescence techniques and derivative ultraviolet/visible absorption spectrophotometry. Fluorescence quenching studies that assess the location of the drugs interacting with the membrane were carried out using labeled liposomes with trimethylammonium-diphenylhexatriene (TMA-DPH), a fluorescent probe with well-known membrane localization. Partition of the drugs within membranes was determined by calculating their partition coefficients (K p ) between liposomes and water using derivative ultraviolet/visible absorption spectrophotometry in a temperature range of 37-50°C. The Van't Hoff analysis of the temperature dependence of K p values allowed calculating the membrane-water variation of enthalpy (ΔH w→m) and entropy (ΔS w→m) and consequently the Gibbs free energy (ΔG w→m).
RESULTS: Results indicate that quenching, partitioning and thermodynamic parameters inherent to the interaction of the studied drugs with the membrane mimetic model are deeply dependent on the initial organization of the membrane, on the pH medium and on the physical properties of the drug.
CONCLUSIONS: The interactions between NSAIDs and membranes are manifested as changes in the physical and thermodynamic properties of the bilayers. Depending on the composition and physical state of the membrane and the chemical structure of the NSAID, the interaction can support or prevent drug activity or toxicity.