腹腔内热灌注阿霉素：大鼠模型中的药代动力学、代谢及组织分布

Hyperthermic intraperitoneal doxorubicin: pharmacokinetics, metabolism, and tissue distribution in a rat model.

作者信息

Jacquet P, Averbach A, Stuart O A, Chang D, Sugarbaker P H

机构信息

The Washington Cancer Institute, Washington Hospital Center, DC 20010, USA.

出版信息

Cancer Chemother Pharmacol. 1998;41(2):147-54. doi: 10.1007/s002800050721.

DOI:10.1007/s002800050721

PMID:9443628

Abstract

BACKGROUND

The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model.

METHODS

Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 degrees C) i.p. doxorubicin; group HT received hyperthermic (43 degrees C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC.

RESULTS

No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001).

CONCLUSION

Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder.

摘要

背景

包括阿霉素在内的几种抗癌药物的细胞毒性作用可通过热疗增强。本研究的目的是评估热疗对啮齿动物模型中腹腔内（i.p.）阿霉素的药代动力学、代谢及组织分布的影响。

方法

将20只Sprague-Dawley大鼠按2mg/kg的剂量在60分钟内腹腔注射阿霉素。根据腹腔灌洗液温度将大鼠随机分为两组：NT组接受常温（37℃）腹腔注射阿霉素；HT组接受热疗（43℃）腹腔注射阿霉素。在腹腔化疗过程中，每10分钟采集一次腹腔液和血液样本。操作结束时，处死大鼠并收集组织样本（肝脏、脾脏、小肠、网膜、膀胱、膈肌、腹壁、心脏）。通过高效液相色谱法测定腹腔液、血浆和组织中阿霉素及其糖苷配基代谢物的浓度。

结果

NT组和HT组之间腹腔液阿霉素和血浆阿霉素的曲线下面积（AUC）无显著差异。NT组的AUC比值（AUC腹腔液/AUC血液）为87.9，HT组为82.9。HT组所有腹腔内组织的阿霉素浓度均升高。脾脏（P = 0.03）、小肠（P = 0.03）和网膜（P = 0.03）的这些差异具有统计学意义。在操作的前10分钟内，两组血浆中均检测到阿霉素糖苷配基。与NT组相比，HT组血浆糖苷配基AUC显著增加（P < 0.001）。HT组所有组织的糖苷配基浓度均升高。肝脏（P < 0.001）和膀胱（P < 0.001）的这种差异具有统计学意义。