Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
J Pharm Biomed Anal. 2013 Jan;72:145-9. doi: 10.1016/j.jpba.2012.10.005. Epub 2012 Oct 16.
Treosulfan (TREO) is an alkylating agent registered for treatment of advanced platin-resistant ovarian carcinoma. Nowadays, TREO is increasingly applied iv in high doses as a promising myeloablative agent with low organ toxicity in children. Under physiological conditions it undergoes pH-dependent transformation into epoxy-transformers (S,S-EBDM and S,S-DEB). The mechanism of this reaction is generally known, but not its kinetic details. In order to investigate kinetics of TREO transformation, HPLC method with refractometric detection for simultaneous determination of the three analytes in one analytical run has been developed for the first time. The samples containing TREO, S,S-EBDM, S,S-DEB and acetaminophen (internal standard) were directly injected onto the reversed phase column. To assure stability of the analytes and obtain their complete resolution, mobile phase composed of acetate buffer pH 4.5 and acetonitrile was applied. The linear range of the calibration curves of TREO, S,S-EBDM and S,S-DEB spanned concentrations of 20-6000, 34-8600 and 50-6000 μM, respectively. Intra- and interday precision and accuracy of the developed method fulfilled analytical criteria. The stability of the analytes in experimental samples was also established. The validated HPLC method was successfully applied to the investigation of the kinetics of TREO activation to S,S-EBDM and S,S-DEB. At pH 7.4 and 37 °C the transformation of TREO followed first-order kinetics with a half-life 1.5h.
曲奥舒凡（TREO）是一种烷化剂，已注册用于治疗晚期铂类耐药卵巢癌。如今，TREO 越来越多地以高剂量静脉内给药，作为一种有前途的低器官毒性骨髓清除剂在儿童中应用。在生理条件下，它会发生 pH 依赖性转化为环氧化物转化剂（S,S-EBDM 和 S,S-DEB）。该反应的机制通常是已知的，但动力学细节尚不清楚。为了研究 TREO 转化的动力学，首次开发了一种 HPLC 方法，该方法带有折射检测，可在一次分析运行中同时测定三种分析物。将含有 TREO、S,S-EBDM、S,S-DEB 和对乙酰氨基酚（内标）的样品直接注入反相柱。为了确保分析物的稳定性并获得其完全分离，应用了由醋酸盐缓冲液 pH 4.5 和乙腈组成的流动相。TREO、S,S-EBDM 和 S,S-DEB 的校准曲线的线性范围分别为 20-6000、34-8600 和 50-6000 μM。所开发方法的日内和日间精密度和准确度符合分析标准。还确定了实验样品中分析物的稳定性。验证后的 HPLC 方法成功应用于 TREO 向 S,S-EBDM 和 S,S-DEB 转化动力学的研究。在 pH 7.4 和 37°C 下，TREO 的转化遵循一级动力学，半衰期为 1.5 小时。
