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Cyclosporine Binds to the Neutral Lipid and Potentially Other Binding Sites of Lipid Transfer Protein I

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Abstract

Purpose. The objective of this study was to determine if cyclosporine (CSA) binds directly to the neutral lipid-binding site of lipid transfer protein I (LTP I).

Methods. This was accomplished by determining LTP I concentrations and cholesteryl esters (CE) and CSA radioactivity of eluted fast protein liquid chromatography (FPLC) fractions following an injection of different treatment groups (i.e., LTP I alone, 3H-CE liposomes alone, 3H-CSA liposomes alone, 3H-CE liposomes + LTP I, and 3H-CSA liposomes + LTP I) onto an FPLC column. Our hypothesis is that CSA will bind to the neutral lipid-binding site of LTP I because of its high solubility/interaction with cholesterol and triglycerides.

Results. Coincubation of LTP I with 3H-CE liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and the appearance of a broad LTP I peak at fractions 30-34 compared to control. Coincubation of LTP I with 3H-CSA liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and fraction 30 compared to control. In addition, 30% of the original radioactivity associated with 3H-CSA liposomes was found coeluted with the unbound LTP I peak at fraction 10. Taken together, these findings suggest that CSA does bind to the neutral lipid-binding site of LTP I but may also bind to other regions along the LTP I molecule.

Conclusions. We have determined that LTP I mediated transfer of CSA between lipoproteins may be a result of the direct binding of CSA to LTP I at both its neutral binding site and potentially other binding sites along the molecule. These findings provide further evidence that the distribution/redistribution of drugs among plasma lipoproteins facilitated by LTP I may serve as a possible mechanism for determining the ultimate fate of drug compounds

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  1. Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada

    Mona Kwong & Kishor M. Wasan

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  1. Mona Kwong
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  2. Kishor M. Wasan
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Correspondence to Kishor M. Wasan.

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Kwong, M., Wasan, K.M. Cyclosporine Binds to the Neutral Lipid and Potentially Other Binding Sites of Lipid Transfer Protein I. Pharm Res 20, 1009–1014 (2003). https://doi.org/10.1023/A:1024454105124

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  • DOI: https://doi.org/10.1023/A:1024454105124

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