Vol. 55, Issue 1, 32-38, January 1999

Interactions of Cyclosporin A with Phospholipid Membranes: Effect of Cholesterol

Tim Söderlund, Jukka Y. A. Lehtonen, and Paavo K. J. Kinnunen

Helsinki Biophysics and Biomembrane Research Group, Department of Medical Chemistry, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

Cyclosporin A (CsA) is a highly hydrophobic drug used to prevent graft rejection after organ transplantation. Interactions of CsA with phosphatidylcholine as well as with binary mixtures containing phosphatidylcholine and cholesterol were investigated by measuring the penetration of CsA into lipid monolayers at an air/water interface, by differential scanning calorimetry, and by imaging with fluorescence microscopy the effects of CsA on the lateral distribution of a fluorescent probe, 1-palmitoyl-2-(N-4-nitrobenz-2-oxa-1,3-diazol)aminocaproyl-phosphocholine, in monolayers. Film penetration studies revealed the association of CsA with lipids to be a biphasic process. Cholesterol diminished the intercalation of CsA into the monolayer at surface pressures of >19 mN/m. CsA broadened the main transition of dimyristoylphosphatidylcholine (DMPC)/-cholesterol (10:1, mol/mol) multilamellar vesicles. The behavior of the transition enthalpy was more complex; the behavior of DMPC/-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 tertiary alloy. Influence of CsA on lateral organization could be verified for lipid domains observed by fluorescence microscopy of lipid monolayers. More specifically, CsA altered the distribution of 1-palmitoyl-2-(N-4-nitrobenz-2-oxa-1,3-diazol)aminocaproyl-phosphocholine in a dipalmitoylphosphatidylcholine film and in DPPC/-cholesterol (88:10, mol/mol) mixtures in a manner 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.