Influence of Overt Diabetes Mellitus on Cyclosporine Pharmacokinetics in a Canine Model

BACKGROUND/AIMS Diabetic patients usually require more medications than their nondiabetic counterparts. This work examined the effect of hyperglycemia on the pharmacokinetic properties of cyclosporine in a diabetic dog model. MAIN METHODS Diabetes was induced using a streptozotocin/alloxan combination and verified by measuring the serum glucose level. Cyclosporine was administered as a bolus intravenous dose of 5 mg/kg, and blood samples were collected at different time points for determining drug concentrations and biochemical analyses. RESULTS Diabetic dogs showed a significant increase in total body clearance of cyclosporine compared to healthy controls (0.457 L hr(-1)Kg(-1) versus 0.201 L hr(-1)Kg(-1), P = .0019) and a decrease in its biological half-life (9.32 hours versus 22.56 hours, P = .0125). In addition, diabetic animals exhibited a higher total cholesterol (7.20 +/- 0.62 mmol/L and 5.28 +/- 0.36 mmol/L; P < .05) as well as more serum low density lipoproteins (4.45 +/- 0.72 mmol/L versus 1.06 +/- 0.10 mmol/L; P < .05). CONCLUSION Overt diabetes alters cyclosporine disposition by modulating its clearance. Abnormalities in the lipid profile, among other factors, may contribute to the accelerated metabolic degradation of cyclosporine under hyperglycemic conditions.