Effect of streptozotocin-induced hyperglycaemia on intravenous pharmacokinetics and acute cardiotoxicity of doxorubicin in rats
Abstract
The present study was designed to investigate the pharmacokinetics and acute cardiotoxicity of doxorubicin (DOX) after intravenous (i.v.) administration (15 mg kg-1) to streptozotocin (STZ)-induced hyperglycaemic and normoglycaemic male Wistar albino rats. In STZ diabetic rats the area under the serum DOX time-concentration curve (AUC0-24 (h)) increased (13.35 ± 1.33 compared with 7.13 ± 0.71 μg h-1 ml-1; P < 0.0001) and plasma and renal DOX clearance decreased. The DOX accumulation in STZ-induced diabetic rat heart (12.7 ± 1.2 μg g g-1) was increased (P < 0.05) compared with non-diabetic hearts (11.0 ± 0.9 μg/g), 24 h after DOX administration. Serum creatine phosphokinase (CPK) activity showed 25% increase in peak level in STZ diabetic rats compared to non-diabetic rats. DOX produced a reduction in heart rate of anaesthetized non-diabetic (20%) and diabetic (14%) rats 1 and 2 h after its administration, respectively. Isolated atria of diabetic rats were more sensitive to the negative chronotropic effect of DOX (150 μM). These preliminary results indicate that hyperglycaemia may alter the pharmacokinetics and acute cardiotoxicity of DOX and suggest that i.v. doses of DOX in diabetic patients may need to be modified if the present data could be extrapolated to humans.