Glehen O, Stuart O A, Mohamed F, Sugarbaker P H
Surgical Department, Centre Hospitalo-Universitaire Lyon Sud, 69495 Pierre Bénite, France.
Cancer Chemother Pharmacol. 2004 Jul;54(1):79-84. doi: 10.1007/s00280-004-0779-0. Epub 2004 Mar 26.
Peritoneal surface malignancy is a common manifestation of failure of treatment for abdominal cancers. Best results of treatment have been achieved with complete cytoreduction followed by heated intraoperative chemotherapy. Melphalan is a chemotherapeutic agent that shows increased pharmacological activity with heat. But the combination of intraperitoneal administration and heat have never been tested for this drug. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics and tissue distribution of intraperitoneal melphalan in a rodent model.
Melphalan was given by the intraperitoneal route to 20 Sprague-Dawley rats at a dose of 12 mg/kg over 90 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (33.5 degrees C) melphalan; group HT received hyperthermic (42 degrees C) melphalan. During the course of intraperitoneal chemotherapy, peritoneal fluid and blood were sampled at 5, 15, 30, 60 and 90 min. At the end of procedure, the rats were killed and tissues samples (heart, liver, ileum, jejunum, colon, omentum, and abdominal wall) were collected. Concentrations of melphalan were determined in peritoneal fluid, plasma, and tissues by high-performance liquid chromatography.
The area under the curve (AUC) of peritoneal fluid melphalan was significantly lower in the HT group than in the NT group ( P=0.001), whereas no significant difference in plasma AUC was found. AUC ratios (AUC peritoneal fluid/AUC plasma) were 12.1 for the NT group and 12.3 for the HT group. The mean time to reach the plasma peak was shorter in the HT group than in the NT group ( P=0.004). The HT group exhibited increased melphalan concentrations in all intraabdominal tissues. These differences were significant for the ileum ( P=0.03) and jejunum ( P=0.04).
Hyperthermia affected the pharmacokinetics of intraperitoneal melphalan by decreasing the AUC of peritoneal fluid melphalan without increasing the plasma AUC. It increased intraabdominal tissue concentrations.
腹膜表面恶性肿瘤是腹部癌症治疗失败的常见表现。通过彻底的细胞减灭术并辅以术中热化疗已取得了最佳治疗效果。美法仑是一种化疗药物，加热后其药理活性会增强。但该药物腹腔给药与热疗联合应用的效果从未得到过测试。本研究的目的是在啮齿动物模型中评估热疗对腹腔内美法仑药代动力学及组织分布的影响。
将20只Sprague-Dawley大鼠腹腔注射美法仑，剂量为12mg/kg，持续90分钟。根据腹腔灌洗液温度将大鼠随机分为两组：NT组接受常温（33.5℃）美法仑；HT组接受热（42℃）美法仑。在腹腔化疗过程中，于5、15、30、60和90分钟采集腹腔液和血液样本。手术结束时，处死大鼠并收集组织样本（心脏、肝脏、回肠、空肠、结肠、网膜和腹壁）。采用高效液相色谱法测定腹腔液、血浆和组织中美法仑的浓度。
HT组腹腔液中美法仑的曲线下面积（AUC）显著低于NT组（P = 0.001），而血浆AUC无显著差异。NT组和HT组的AUC比值（AUC腹腔液/AUC血浆）分别为12.1和12.3。HT组达到血浆峰值的平均时间短于NT组（P = 0.004）。HT组所有腹腔内组织中美法仑浓度均升高。回肠（P = 0.03）和空肠（P = 0.04）的这些差异具有统计学意义。
热疗通过降低腹腔液中美法仑的AUC而不增加血浆AUC来影响腹腔内美法仑的药代动力学。它增加了腹腔内组织浓度。
