Colombo T, Gonzalez Paz O, Zucchetti M, Maneo A, Sessa C, Goldhirsch A, D'Incalci M
Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
Ann Oncol. 1996 Oct;7(8):801-5. doi: 10.1093/oxfordjournals.annonc.a010758.
Inhibition of Pgp can affect the distribution and the pharmacokinetics of anthracyclines, causing marked changes in their toxicity. Since both paclitaxel and cremophor are substrates of Pgp, it was hypothesized that they could modify the pharmacokinetics of anthracyclines in a similar fashion.
To evaluate whether pretreatment of mice with cremophor or paclitaxel dissolved in cremophor could induce changes in the distribution of epidoxorubicin (EpiDx).
Male CDF1 mice were treated with ethanol or cremophor or paclitaxel and 30 min later with EpiDx (15 mg/kg i.v.). EpiDx serum and tissue levels were determined at several time points after EpiDx treatment by high pressure liquid chromotagraphy (HPLC) assay coupled with fluorimetric detection.
Pretreatment with paclitaxel dissolved in cremophor induced a highly significant increase in EpiDx levels in all tissues examined including heart. At 8 h heart levels in mice treated with EpiDx alone, EpiDx and cremophor and EpiDx and paclitaxel were 8.3 micrograms/g, 10.9 micrograms/g and 16.7 micrograms/g (P < 0.01), respectively. Cremophor alone induced a similar increase in spleen EpiDx levels but had only a moderate effect on heart and lung EpiDx levels. Levels of doxorubicin (Dx) aglycone in kidney and liver of mice treated with paclitaxel and EpiDx were higher than those in mice treated with EpiDx alone.
A pharmacokinetic interaction between paclitaxel and EpiDx was clearly demonstrated in mice. The much higher tissue levels of EpiDx after paclitaxel pretreatment may be the reason for the increased toxicity of EpiDx when administered soon after paclitaxel.
P-糖蛋白（Pgp）的抑制作用可影响蒽环类药物的分布及药代动力学，导致其毒性发生显著变化。由于紫杉醇和聚氧乙烯蓖麻油都是Pgp的底物，因此推测它们可能以类似方式改变蒽环类药物的药代动力学。
评估用聚氧乙烯蓖麻油溶解的聚氧乙烯蓖麻油或紫杉醇预处理小鼠是否会引起表柔比星（EpiDx）分布的变化。
雄性CDF1小鼠分别用乙醇、聚氧乙烯蓖麻油或紫杉醇处理，30分钟后静脉注射EpiDx（15mg/kg）。通过高压液相色谱（HPLC）分析结合荧光检测，在EpiDx处理后的几个时间点测定EpiDx的血清和组织水平。
用聚氧乙烯蓖麻油溶解的紫杉醇预处理可导致包括心脏在内的所有检测组织中EpiDx水平高度显著升高。在单独用EpiDx处理、EpiDx与聚氧乙烯蓖麻油联合处理以及EpiDx与紫杉醇联合处理的小鼠中，8小时时心脏中的EpiDx水平分别为8.3μg/g、10.9μg/g和16.7μg/g（P<0.01）。单独使用聚氧乙烯蓖麻油可使脾脏中EpiDx水平出现类似升高，但对心脏和肺中EpiDx水平的影响仅为中等程度。用紫杉醇和EpiDx处理的小鼠肾脏和肝脏中多柔比星（Dx）苷元的水平高于单独用EpiDx处理的小鼠。
在小鼠中明确证实了紫杉醇与EpiDx之间存在药代动力学相互作用。紫杉醇预处理后EpiDx组织水平高得多可能是紫杉醇给药后不久给予EpiDx时其毒性增加的原因。
