Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.
Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.
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发表时间：
1994-02
期刊：
影响因子：
11.2
通讯作者：
A. Gabizon;R. Catane;B. Uziely;B. Kaufman;T. Safra;R. Cohen;F. Martín;A. Huang;Y. Barenholz
中科院分区：
文献类型：
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作者：
A. Gabizon;R. Catane;B. Uziely;B. Kaufman;T. Safra;R. Cohen;F. Martín;A. Huang;Y. Barenholz
在临床前研究中，含有聚乙二醇（Doxil）的多柔比星脂质体制剂显示出在血浆中的长循环时间、在鼠肿瘤中的增强的积累以及优于游离（未包封的）多柔比星（DOX）的上级治疗活性。本研究的目的是描述癌症患者中Doxil与游离DOX相比的药代动力学特征，并检查其在恶性积液中的蓄积。在7名患者中分析了阿霉素和/或脂质体相关阿霉素的药代动力学，这些患者在注射等效剂量的游离DOX和Doxil后，以及在另外一组9名患者中仅注射Doxil后。检查了两个剂量水平，25和50 mg/m2。如果可能，还测量了恶性积液中的药物水平。Doxil的血浆消除遵循双指数曲线，半衰期为2和45 h（中位值），大部分剂量在较长的半衰期内从血浆中清除。注射Doxil后，血浆中检测到的药物几乎100%为脂质体包封形式。缓慢的血浆清除率（Doxil为0.1升/小时，游离DOX为45升/小时）和小的分布容积（Doxil为4升，游离DOX为254升）是Doxil的特征。在Doxil治疗患者的尿液中检测到阿霉素代谢物，其模式与游离DOX报告的模式相似，尽管药物和代谢物的总体尿液排泄显著减少。Doxil治疗导致恶性积液中药物水平增加4至16倍，在注射后3至7天达到峰值。与Doxil相关的口腔炎发生在15例可评价患者中的5例中，并且似乎是重度预治疗患者中最显著的副作用。本研究的结果与临床前发现一致，表明使用Doxil时多柔比星的药代动力学发生了显著改变，并遵循脂质体载体所指示的模式。恶性胸腔积液中药物蓄积的增强与脂质体在循环中的寿命明显相关。需要进一步的临床研究来确定这些发现与脂质体改变阿霉素递送至实体瘤的能力及其抗肿瘤活性模式的相关性。
In preclinical studies, a doxorubicin liposome formulation containing polyethylene-glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-associated doxorubicin were analyzed in seven patients after injections of equivalent doses of free DOX and Doxil and in an additional group of nine patients after injection of Doxil only. Two dose levels were examined, 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 liter/h for Doxil versus 45 liters/h for free DOX) and a small volume of distribution (4 liters for Doxil versus 254 liters for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clinical investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.