Interactions of cyclosporin A with phospholipid membranes: Effect of cholesterol

Cyclosporin A (CsA) is a highly hydrophobic drug used to prevent graft reje ction after organ transplantation. Interactions of CsA with phosphatidylcho line as well as with binary mixtures containing phosphatidylcholine and cho lesterol were investigated by measuring the penetration of CsA into lipid m onolayers at an air/water interface, by differential scanning calorimetry, and by imaging with fluorescence microscopy the effects of CsA on the later al distribution of a fluorescent probe, 1-palmitoyl-2-(N-4-nitrobenz-2-oxa- 1,3-diazol)aminocaproyl-phosphocholine, in monolayers. Film penetration stu dies revealed the association of CsA with lipids to be a biphasic process. Cholesterol diminished the intercalation of CsA into the monolayer at surfa ce pressures of >19 mN/m(-). CsA broadened the main transition of dimyristo ylphosphatidylcholine (DMPC)/beta-cholesterol (10:1, mol/mol) multilamellar vesicles. The behavior of the transition enthalpy was more complex; the be havior of DMPC/beta-cholesterol multilamellar vesicles in the X-CSA of 0 to 0.1 showed at most ratios a increase, but several well distinct dips were observed. The results are interpreted in terms of regular structures in ter tiary alloy. Influence of CsA on lateral organization could be verified for lipid domains observed by fluorescence microscopy of lipid monolayers. Mor e specifically, CsA altered the distribution of 1-palmitoyl-2-(N-4-nitroben z-2oxa-1,3-diazol)aminocaproyl-phosphocholine in a dipalmitoylphosphatidylc holine film and in DPPC/beta-cholesterol (88:10, mol/mol) mixtures in a man ner that suggests that CsA partitions into the boundaries between fluid and gel domains. To our knowledge; this constitutes the first demonstration of a change in lipid domain morphology to be induced by a drug molecule.