Receptor-mediated cellular uptake of cyclosporine.

THE PROCESS of cellular uptake and metabolism of cyclosporine (CsA) is poorly understood. Earlier studies in this laboratory indicated that transport of CsA in blood occurs in association with plasma lipoproteins, with low density lipoprotein (LDL) and high density lipoprotein (HOL) carrying about 32% each of the total CsA in blood. This observation suggests the possibility that the cellular uptake of CsA may occur through the LDL receptor pathway. To further identify this phenomenon, we incubated CsA-LOL complex with freshly isolated peripheral blood lymphocytes (PBL) and also with PBL in which LDL receptors synthesis was enhanced by incubation in lipid free serum. Results of these experiments show that cellular uptake of CsA is increased about 25% in cells incubated in lipid-free serum relative to controls. This increased uptake of CsA could be in part due to the proliferation of LDL receptors in the stimulated cells. Since at least 32% of the drug circulates in association with LDL, this pathway provides an important mechanism for the meta bolism of CsA. The aims of this study were to examine the kinetics of binding and uptake of CsA by the human peripheral blood lymphocytes. and the enhancement of CsA uptake by peripheral blood lymphocytes via LOL receptor pathway. Cyclosporine (CsA) is widely used in transplantation as the immunosuppressive agent of choice. In our earlier studies. we have shown that transport of CsA in blood occurs mainly in association with plasma lipoproteins. 70% of the drug being in LDL and HOL fractions.! This suggests that cellular uptake and metabolism of CsA may. at least in part. follow the lipoprotein metabolism. specifically. the LOLreceptor mediated pathway.