A precise pharmacodynamic study showing the advantage of a marked reduction in cardiotoxicity in continuous infusion of doxorubicin

We have already shown that the antileukemic activity of daunorubicin that had been reported to be dependent on the area under the concentration - time curve (AUC) was actually peak concentration (Cmax) dependent. The antitumor activity of doxorubicin (DXR) has also been reported to be dependent on A...

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Bibliographic Details
Published in:Leukemia & lymphoma 2006-08, Vol.47 (8), p.1599-1607
Main Authors: Ishisaka, Taizo, Kishi, Shinji, Okura, Kiyotaka, Horikoshi, Motosaburo, Yamashita, Taro, Mitsuke, Yasuhiko, Shimizu, Hiromasa, Ueda, Takanori
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - analysis
Animals
Anthracycline
Area Under Curve
AUC
Cell Line, Tumor
Cells, Cultured
Doxorubicin - administration & dosage
Doxorubicin - pharmacokinetics
Heart Diseases - chemically induced
Infusion Pumps
Leukemia - complications
Leukemia - drug therapy
max
Metabolic Clearance Rate
Mice
Myocytes, Cardiac - drug effects
pharmacodynamics
Pharmacokinetics
Rats
Rats, Wistar
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Summary:We have already shown that the antileukemic activity of daunorubicin that had been reported to be dependent on the area under the concentration - time curve (AUC) was actually peak concentration (Cmax) dependent. The antitumor activity of doxorubicin (DXR) has also been reported to be dependent on AUC, whereas its cumulative cardiotoxicity has been reported to be Cmax dependent. In this study, we evaluated whether the antileukemic and cardiotoxic effects of DXR were AUC or Cmax dependent, and compared their cytotoxic effects, utilizing the computer-controlled in vitro pharmacokinetic simulation system or a conventional culture system for a leukemic cell line and measuring the intracellular ATP amount or the proportion of beating cells for the cardiotoxicity. In leukemic cells, the cytotoxic rate decreased as the simulated infusion time or exposure time increased with the same AUC value in the simulation and conventional culture system (P < 0.05 and
ISSN:1042-8194
1029-2403
DOI:10.1080/10428190600580767