Platel D, Pouna P, Bonoron-Adèle S, Robert J
Institut Bergonié, Bordeaux, France.
Toxicol Appl Pharmacol. 2000 Mar 1;163(2):135-40. doi: 10.1006/taap.1999.8847.
Paclitaxel strongly potentiates the cardiotoxicity of doxorubicin in the clinical setting. In this study, we aimed (1) to determine whether this potentiation could be reproduced in an ex vivo model and, if so, (2) to select drugs and protocols that did not cause this potentiation. The effect of paclitaxel and docetaxel on the cardiotoxicity induced by doxorubicin and epirubicin was studied using the model of isolated perfused rat heart. Cardiac performances were evaluated after several combination protocols administered every 2 days over a period of 12 days, and anthracycline concentrations in the heart and liver were determined on Day 12. When administered simultaneously, paclitaxel strongly potentiated the cardiotoxicity of doxorubicin ex vivo, and this effect was not due to Cremophor EL, the solvent used in the formulation of paclitaxel. The potentiation of anthracycline cardiotoxicity could be avoided by the replacement of doxorubicin by epirubicin, and/or of paclitaxel by docetaxel. Cardiotoxic potentiation was also avoided by the introduction of a 24-h lag time between the repetitive injections of doxorubicin and docetaxel. The concentration of doxorubicin and its cardiotoxic metabolite, doxorubicinol, in the heart and liver was not significantly altered by the taxanes, but that of epirubicin was increased twofold both in the heart and the liver. These results show that the potentiation of doxorubicin-induced cardiotoxicity by paclitaxel can be reproduced with an ex vivo model, and that it is not related to an increase in tissue concentration of the drug or active metabolite. Our model, therefore, may be useful for the selection of anthracycline-containing protocols with no increased risk of cardiotoxicity for the patients.
在临床环境中，紫杉醇会显著增强阿霉素的心脏毒性。在本研究中，我们旨在：（1）确定这种增强作用能否在体外模型中重现；如果可以，（2）选择不会引起这种增强作用的药物和方案。使用离体灌注大鼠心脏模型研究了紫杉醇和多西他赛对阿霉素和表阿霉素诱导的心脏毒性的影响。在12天的时间里，每2天给予几种联合方案后评估心脏功能，并在第12天测定心脏和肝脏中的蒽环类药物浓度。同时给药时，紫杉醇在体外显著增强了阿霉素的心脏毒性，且这种作用并非由于紫杉醇制剂中使用的溶剂聚氧乙烯蓖麻油（Cremophor EL）。用表阿霉素替代阿霉素和/或用多西他赛替代紫杉醇可避免蒽环类药物心脏毒性的增强。在重复注射阿霉素和多西他赛之间引入24小时的延迟时间也可避免心脏毒性增强。紫杉烷类药物并未显著改变心脏和肝脏中阿霉素及其心脏毒性代谢产物阿霉素醇的浓度，但表阿霉素在心脏和肝脏中的浓度均增加了两倍。这些结果表明，紫杉醇对阿霉素诱导的心脏毒性的增强作用可以在体外模型中重现，且与药物或活性代谢产物的组织浓度增加无关。因此，我们的模型可能有助于为患者选择心脏毒性风险未增加的含蒽环类药物方案。
