Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Int J Pharm. 2015 Feb 1;479(1):23-7. doi: 10.1016/j.ijpharm.2014.12.025. Epub 2014 Dec 20.
Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures.
5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 °C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal(®) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 °C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2].
The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS-HIPEC procedures.
奥沙利铂在细胞减灭术和腹腔内热灌注化疗（CRS-HIPEC）中越来越成为治疗腹膜恶性肿瘤的化疗药物选择。奥沙利铂在含氯介质中不稳定，导致在这些程序中使用 5%葡萄糖作为载体溶液。在 30 分钟至 90 分钟的灌注时间内，腹膜暴露于 5%葡萄糖中会导致严重的高血糖和电解质紊乱。这可能导致显著的术后发病率和死亡率。为了确定是否可以使用更安全的含氯载体溶液，我们报告了在含氯和缺氯载体溶液中奥沙利铂稳定性的体外分析结果，并讨论了其对基于奥沙利铂的 CRS-HIPEC 程序的影响。
将 5 毫克奥沙利铂加入 42°C 的各种载体溶液 50 毫升中：5%葡萄糖、0.9%氯化钠、林格乳酸盐、Dianeal®PD4 葡萄糖 1.36%腹膜透析溶液和 0.14 M 无菌磷酸盐缓冲液 pH 值 7.4。在标准化间隔收集样品，并使用与紫外线检测器（HPLC-UV）耦合的稳定指示高效液相色谱法（HPLC-UV）测定奥沙利铂浓度；使用 HPLC-质谱法鉴定奥沙利铂降解产物。
在 5%葡萄糖中，奥沙利铂浓度在 2 小时内保持稳定。氯离子浓度的增加与降解速率的增加有关；然而，这种降解在 30 分钟后（大多数临床 CRS-HIPEC 方案中的标准腹膜灌注时间）限制在<10%降解，在 42°C 下 120 分钟后限制在<20%降解。此外，奥沙利铂的降解与它的活性药物形式[Pt(dach)Cl2]的形成有关。
在测试的体外条件下，含氯载体溶液的使用对奥沙利铂的浓度没有明显影响。氯离子似乎促进了奥沙利铂的活性细胞毒性药物形式的形成，因此可以增强其细胞毒性作用。这些数据表明，更生理的含氯载体溶液可以安全有效地用作 CRS-HIPEC 程序中奥沙利铂的介质。
