N.N. Petrov National Medical Research Center of Oncology, 197758 Saint Petersburg, Russia.
Institute of Toxicology, Federal Medical Biological Agency, 192019 Saint Petersburg, Russia.
Molecules. 2020 Oct 15;25(20):4733. doi: 10.3390/molecules25204733.
Hyperthermic intraperitoneal chemoperfusion (HIPEC) is an established form of locoregional chemotherapy of peritoneum tumors. However, its efficacy and safety status remain a controversy, partially, due to scarce data on pharmacokinetics and toxicity profile of drugs under HIPEC. In the current study, 24 female Wistar rats were randomly assigned to receive cisplatin as HIPEC ( = 12, 20 mg/kg) or intravenously (i.v., = 9, 4 mg/kg). The subgroups of three animals were used for the initial, intermediate, and late phases of the pharmacokinetic assessment. The animals were sacrificed on days 1 and 5. Blood, liver, kidney, and ovaries were evaluated for platinum content. Histological and immunohistochemical evaluation was undertaken in the liver and kidney. A trend for higher blood plasma platinum levels was observed for HIPEC compared to i.v. Significantly lower ( < 0.001) relative platinum binding to the proteins was observed in HIPEC animals compared to the i.v. administration. A five-fold higher concentration of cisplatin in HIPEC resulted in a ca. 2.5-fold increase in total blood platinum and ca. two-fold increase in blood ultrafitrable platinum ("free" Pt). Immunohistochemistry revealed higher kidney and liver damage after i.v. administration of cisplatin compared to HIPEC, although a five-fold higher dose of cisplatin was applied in HIPEC. Together with relatively lower absorption to the systemic circulation in HIPEC, higher protein binding is probably the primary reason for lower observed toxicity in HIPEC animals.
腹腔内热灌注化疗（HIPEC）是一种治疗腹膜肿瘤的局部化疗方法。然而，由于 HIPEC 下药物药代动力学和毒性特征的数据稀缺，其疗效和安全性仍存在争议。在本研究中，24 只雌性 Wistar 大鼠被随机分为 HIPEC 组（=12，20mg/kg）或静脉组（=9，4mg/kg）接受顺铂治疗。三个亚组的 3 只动物用于药代动力学评估的初始、中期和晚期阶段。动物在第 1 天和第 5 天被处死。评估血液、肝脏、肾脏和卵巢中的铂含量。对肝脏和肾脏进行组织学和免疫组织化学评估。与静脉组相比，HIPEC 组的血液血浆铂水平呈上升趋势。与静脉组相比，HIPEC 组动物中相对较低（<0.001）的铂与蛋白质结合。HIPEC 中顺铂浓度增加五倍，导致总血液铂增加约 2.5 倍，血液超滤铂（“游离”Pt）增加约 2 倍。免疫组化显示，与 HIPEC 相比，静脉注射顺铂后肾脏和肝脏损伤更高，尽管 HIPEC 中应用了五倍剂量的顺铂。与 HIPEC 中相对较低的吸收到体循环相比，较高的蛋白结合可能是 HIPEC 动物中观察到的毒性较低的主要原因。
