Fenamates are nonsteroidal anti-inflammatory drugs (NSAID), usually prescribed to treat pain and inflammation and, like other NSAIDs, to inhibit cyclooxygenases. They have also been proposed to show anti-epileptic and neuroprotective effects. In the current work, the interaction of several fenamates with phospholipid membranes was studied using various NMR techniques. One of the most important properties of membranes that influences the function and localization of proteins is their fluidity. Changes in membrane fluidity can also affect a drug's ability to bind to and permeate through the membrane, which influences its efficacy. We studied the interaction of several fenamates with zwitterionic palmitoyloleoylphosphatidylcholine (POPC) membranes. Based on 1H NMR-induced chemical shift data and quantitative analysis of 1H MAS NOESY cross-relaxation rates, three fenamates (mefenamic, flufenamic and tolfenamic acid) were shown to penetrate the lipid membrane and are dynamically distributed within the bilayer. The average position of each drug in the lipid-water interface was also estimated from these measurements. 2H NMR data showed that binding of tolfenamic and mefenamic acid increases lipid chain order, while flufenamic acid slightly decreased lipid chain order in the lower segments of POPC membranes.
