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 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 <0.01, respectively). The intracellular ATP and proportion of beating cells also increased with prolonged DXR exposure time with the same constant concentration - time product value (P < 0.05 and <0.0001, respectively) in heart cells. These results indicated that both the antileukemic effects and the cardiotoxicity were Cmax dependent. However, a comparison of the two showed that cardiotoxicity was more Cmax dependent than the antileukemic effect. These results suggested that the continuous infusion treatment schedule of DXR may have the clinical advantage of reducing cardiotoxicity more markedly than the antileukemic effect.
Ishisaka
Taizo
T
First Department of Internal Medicine, Faculty of Medical Sciences, Fukui University, Fukui, Japan.
Kishi
Shinji
S
Okura
Kiyotaka
K
Horikoshi
Motosaburo
M
Yamashita
Taro
T
Mitsuke
Yasuhiko
Y
Shimizu
Hiromasa
H
Ueda
Takanori
T
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D019540:Area Under Curve; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006331:Heart Diseases / Q000139:chemically induced*; D007260:Infusion Pumps; D007938:Leukemia / Q000150:complications / Q000188:drug therapy; D008657:Metabolic Clearance Rate; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D010599:Pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D004317:Doxorubicin; D000255:Adenosine Triphosphate