Methyl-beta-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in therabbit

The purpose of this work was to determine the pharmacokinetics and the tiss ue concentrations of methyl-beta-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combinat ion. MEBCD (300 mg/kg) and DOX (1 mg/kg;) were intravenously injected to wh ite New Zealand rabbits and blood samples were obtained over a 48-h period after administration. After this period, administration was repeated and an imals were killed 1, 2 or 4 h after injection. Heart, liver and kidney were then removed. MEBCD and DOX analysis in plasma and tissues was performed u sing two HPLC methods with fluorimetric detection. MEBCD pharmacokinetic pr ofile was consistent with a two-compartment model (t(1/2) alpha: 30 min; t( 1/2) beta: 7 h). Go-administration with DOX did not modify the main pharmac okinetic parameters of MEBCD. However, C-5 min, t(1/2) alpha, t(1/2) beta a nd AUC(infinity) were decreased by the co-administration of DOX with MEBCD compared to DOX alone. Assays of excised tissues showed that DOX enhanced t he cardiac, renal and hepatic concentrations of MEBCD. On the other hand, M EBCD did not alter the cardiac distribution of DOX, while renal and hepatic distribution profiles were modified. In this study, the pharmacokinetic pa rameters of MEBCD injected intravenously were determined for the first time . DOX did not enhance MEBCD pharmacokinetic profile but MEBCD reduced the d istribution half-life of DOX. Tissue determination showed that MEBCD did no t enhanced the cardiac accumulation of DOX, which is auspicious for further in vivo experiments using the co-administration of DOX and MEBCD. (C) 1999 Elsevier Science B.V. All rights reserved.