Influence of overt diabetes mellitus on cyclosporine pharmacokinetics in a canine model.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. alkharfy@ksu.edu.sa
Khalid M
KM
Alkharfy
D000496:Alloxan / Q000008:administration & dosage; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003921:Diabetes Mellitus, Experimental; D004285:Dogs; D007003:Hypoglycemia / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000097:blood; D015233:Models, Statistical; D013311:Streptozocin / Q000008:administration & dosage
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D008077:Lipoproteins, LDL; D013311:Streptozocin; D000496:Alloxan; D016572:Cyclosporine; D002784:Cholesterol