Effect of streptozotocin-induced hyperglycaemia on intravenous pharmacokinetics and acute cardiotoxicity of doxorubicin in rats

The present study was designed to investigate the pharmacokinetics and acut e cardiotoxicity of doxorubicin (DOX) after intravenous (i.v.) administrati on (15 mg kg(-1)) to streptozotocin (STZ)-induced hyperglycaemic and normog lycaemic male Wistar albino rats. In STZ diabetic rats the area under the s erum DOX time-concentration curve (AUC(0-24 h)) increased (13.35 +/- 1.33 c ompared with 7.13 +/- 0.71 mu g h(-1) ml(-1); P < 0.0001) and plasma and re nal DOX clearance decreased. The DOX accumulation in STZ-induced diabetic r at heart (12.7 +/- 1.2 mu g g(-1)) was increased (P < 0.05) compared with n on-diabetic hearts (11.0 +/- 0.9 mu g/g), 24 h after DOX administration. Se rum creatine phosphokinase (CPK) activity showed 25% increase in peak level in STZ diabetic rats compared to non-diabetic rats. DOX produced a reducti on in heart rate of anaesthetized non-diabetic (20%) and diabetic (14%) rat s 1 and 2 h after its administration, respectively. Isolated atria of diabe tic rats were more sensitive to the negative chronotropic effect of DOX (15 0 mu M). These preliminary results indicate that hyperglycaemia may alter t he pharmacokinetics and acute cardiotoxicity of DOX and suggest that i.v. d oses of DOX in diabetic patients may need to be modified if the present dat a could be extrapolated to humans. (C) 2000 Academic Press.