The Effect of Cyclosporine and Methylprednisolone on Plasma Lipoprotein Levels in Rats

Abstract

Background: Cyclosporine and methylprednisolone are potent immunosuppressive agents frequently used in transplant recipients, but their independent and combined effects on plasma lipid metabolism are not fully established. Methods: Male Wistar rats were divided into 10 groups receiving low (15 mg/kg/day cyclosporine, 1 mg/kg/day methylprednisolone) or high (30 mg/kg/day cyclosporine, 2 mg/kg/day methylprednisolone) doses of cyclosporine alone, methylprednisolone alone, the combination of both, or vehicle/saline controls. Plasma lipid and lipoprotein fractions were measured by enzymatic methods and ultracentrifugation. Lipoprotein lipase activity was assayed, and total plasma cyclosporine levels were determined by fluorescence polarization. Results: Cyclosporine significantly increased plasma triglycerides, very-low-density lipoprotein (VLDL) triglycerides, and low-density lipoprotein (LDL) cholesterol, while decreasing high-density lipoprotein (HDL) cholesterol and HDL₂ subfraction. Cyclosporine also decreased plasma lipoprotein lipase activity. Methylprednisolone produced increases in triglycerides and VLDL triglycerides with a decrease in HDL cholesterol, but did not alter lipoprotein lipase activity. The combination of both drugs produced greater increases in triglycerides and VLDL triglycerides than either drug alone, and more pronounced decreases in HDL and HDL₂ cholesterol. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios were elevated only by cyclosporine at both doses. Conclusions: Cyclosporine and methylprednisolone exert independent and additive effects on plasma lipid levels. Cyclosporine-induced hypertriglyceridemia is mediated through decreased lipoprotein lipase activity, while methylprednisolone likely increases VLDL synthesis. Cyclosporine is the primary drug responsible for LDL cholesterol elevation. These findings provide mechanistic insights into immunosuppressive therapy-related dyslipidemia in transplant recipients.

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