Hwang S B, Shen T Y
J Med Chem. 1981 Oct;24(10):1202-11. doi: 10.1021/jm00142a016.
The interaction of the nonsteroidal antiinflammatory drugs (NSAIDS) indomethacin, diflunisal, and flurbiprofen and the active sulfide metabolite of sulindac with phosphatidylcholine (PC) liposomes was investigated using differential scanning calorimetry (DSC). These biologically active structures decrease the phase transition temperature and broaden the transition peak with increasing concentration, but without affecting the enthalpy change for the transition on the thermal scan. A comparison with the effects of the prodrug sulindac and its inactive sulfone metabolite suggests that the main action of NSAIDS on membranes is a reduction of the cooperative interaction between phospholipid molecules. The probable positions of these compounds in the bilayer are inferred from similar DSC effects of several reference compounds whose mode of binding to the PC bilayer have previously been described. The active antiinflammatory structures appear to insert deeply into the hydrocarbon region of the bilayer, whereas the inactive compounds probably bind mainly to the carbonyl region near the surface. Using purple membrane as a model to study the drug effect on protein--protein interaction in this membrane system, low concentrations of active NSAIDS effectively dissociate the bacteriorhodopsin lattice. These results suggest that the active NSAIDS studied here are able to partition deeply into the hydrocarbon region of the bilayer and interact with a membrane protein imbedded inside the bilayer. The prodrug sulindac per se is devoid of any significant membrane effects.
