Methyl-beta-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit.
The purpose of this work was to determine the pharmacokinetics and the tissue concentrations of methyl-beta-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination. MEBCD (200 mg/kg) and DOX (1 mg/kg) were intravenously injected to white New Zealand rabbits and blood samples were obtained over a 48-h period after administration. After this period, administration was repeated and animals 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 using two HPLC methods with fluorimetric detection. MEBCD pharmacokinetic profile was consistent with a two-compartment model (t1/2 alpha: 30 min; t1/2 beta: 7 h). Co-administration with DOX did not modify the main pharmacokinetic parameters of MEBCD. However, C5 min, t1/2 alpha, t1/2 beta and AUCinfinity were decreased by the co-administration of DOX with MEBCD compared to DOX alone. Assays of excised tissues showed that DOX enhanced the cardiac, renal and hepatic concentrations of MEBCD. On the other hand, MEBCD did not alter the cardiac distribution of DOX, while renal and hepatic distribution profiles were modified. In this study, the pharmacokinetic parameters of MEBCD injected intravenously were determined for the first time. DOX did not enhance MEBCD pharmacokinetic profile but MEBCD reduced the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX, which is auspicious for further in vivo experiments using the co-administration of DOX and MEBCD.
Grosse
P Y
PY
Department of Oncological Pharmacology, Pharmacy service, Val d'Aurelle Anticancer Center, parc Euromédecine 34298, Montpellier Cedex 05, France.
Bressolle
F
F
Rouanet
P
P
Joulia
J M
JM
Pinguet
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005470:Fluorometry; D006207:Half-Life; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D014018:Tissue Distribution; D047392:beta-Cyclodextrins
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D004317:Doxorubicin