Membrane effects of antiinflammatory agents. 1. Interaction of sulindac and its metabolites with phospholipid membrane, a magnetic resonance study.

High-resolution proton NMR and spin-label ESR spectroscopies have been applied to examine the interaction of the nonsteroidal antiinflammatory drug sulindac (1) and its active sulfide metabolite (2) and inactive sulfone metabolite (3) with phospholipid membranes. Only weak interactions were observed with 1 and 3, but a strong interaction with 2 was indicated both by specific changes in the proton transverse relaxation rate (1/T2) of different substituents in 2 and by a unique shift in membrane transition temperature in the presence of 2 as measured by the ESR technique. Since the structural differences of these compounds are confined to a single polar substituent, i.e., the oxidation state of the sulfur atom, the strong interaction of the sulfide metabolite (2) with the neutral phospholipid membrane is ascribed to its high partition coefficient in the lipid membrane and its ability to penetrate into the lipid bilayer with the carboxyl group remaining at the polar membrane surface. As evidenced from the ESR spectra of two spin-labels, C5- and C12-doxylstearic acid, no significant change of the membrane fluidity was induced by the interaction of 2 with phospholipid vesicles.