Effects of Low and High Density Lipoproteins on Renal Cyclosporine A and Cyclosporine G Disposition in the Isolated Perfused Rat Kidney

Purpose. This study investigated the effects of low (LDL) and high density lipoproteins (HDL) on renal cyclosporine A (CsA) and cyclosporine G (CsG) disposition in the isolated perfused rat kidney model.Methods. Kidneys were perfused with CsA or CsG in perfusion medium containing 6% protein, bovine serum albumin only (BSA) (Control), LDL (200 mg/dl) and BSA, or HDL (200 mg/dl) and BSA. In vitro protein binding studies were conducted with CsA and CsG in the same media.Results. The unbound fractions (f_u) of CsA and CsG were significantly reduced with LDL and HDL in the perfusion media. In the presence of LDL, f_u for CsA and CsG was 3.9% and 5.9%, respectively. With HDL, f_u was 2.1% for CsA and 1.8% for CsG. f_u for the controls was 14.7% for CsA and 11.9% for CsG. Renal clearance (CL_R) of CsA and CsG was significantly reduced when perfused with perfusion medium containing LDL and HDL. LDL and HDL had similar effects on reducing CsA and CsG CL_R, and were four-fold lower when compared to controls (0.006 Vs. 0.023 ml/min). Renal CsA and CsG tissue (whole organ, cortex and medulla) concentrations were lower than corresponding controls when perfused with LDL or HDL.Conclusions. The interaction of CsA and CsG with LDL and HDL significantly reduced the CL_R and extent of renal tissue distribution of both compounds.