Mohamed Faheez, Marchettini Pierre, Stuart O Anthony, Sugarbaker Paul H
The Washington Cancer Institute, Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010, USA.
Cancer Chemother Pharmacol. 2003 Nov;52(5):405-10. doi: 10.1007/s00280-003-0680-2. Epub 2003 Jul 23.
For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel infused intraperitoneally in two isotonic carrier solutions: 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.
A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal paclitaxel (40 mg/m2) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.
Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=0.0079). No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h. Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=0.0079), 12 h (P=0.0079), and 18 h (P=0.0317). The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=0.0079) and 18 h (P=0.0317). There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191). Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium.
The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity. Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted.
对于已扩散至腹膜表面的癌症，腹腔内给药化疗可使局部药物浓度升高，全身毒性降低。我们使用大鼠模型比较了紫杉醇在两种等渗载体溶液中腹腔内输注后的药代动力学和组织吸收情况：1.5%葡萄糖腹膜透析液（腹膜透析液）和贺斯（6%羟乙基淀粉），一种高分子量溶液。
总共60只Sprague Dawley大鼠根据所给予的载体溶液随机分组。大鼠以每克体重0.1 ml的每种载体溶液给予单剂量腹腔内紫杉醇（40 mg/m²）。每组再根据腹腔内停留时间（3、6、12、18和24小时）进一步随机分组。在实验结束时处死大鼠，完全抽出腹腔液并记录体积。按照标准化方案采集血液和组织样本。通过高效液相色谱法测定腹腔液、血浆和组织中的药物浓度。
在存在贺斯的情况下，腹腔内液体清除率低于存在腹膜透析液的情况。在18小时时，贺斯组腹腔内剩余的平均液体量显著更高（P = 0.0079）。在24小时时，腹膜透析液组没有剩余过多的腹腔液。在3小时（P = 0.0079）、12小时（P = 0.0079）和18小时（P = 0.0317）时，贺斯组的平均血浆紫杉醇浓度显著更低。在12小时（P = 0.0079）和18小时（P = 0.0317）时，贺斯组腹腔内剩余的药物平均总量显著更多。与腹膜透析液（191）相比，贺斯组腹腔液与血浆紫杉醇浓度曲线下面积比增加了105%（391）。在6小时时，腹膜透析液组在结肠、腹壁和心肌中的紫杉醇浓度显著更高。
使用含贺斯载体溶液的腹腔内紫杉醇给药为局部区域杀灭残留肿瘤细胞提供了药理学优势，同时降低了全身毒性。有必要对使用6%高分子量贺斯与化疗药物进行临床研究。
