Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
J Pharm Sci. 2017 Oct;106(10):3156-3160. doi: 10.1016/j.xphs.2017.05.033. Epub 2017 Jul 29.
Treosulfan (TREO) is a prodrug applied in the treatment of ovarian cancer and a myeloablative conditioning prior to stem cell transplantation. A sequential activation of TREO to intermediate monoepoxide (S,S-EBDM) and then to (2S,3S)-1,2:3,4-diepoxybutane (S,S-DEB) involves a nonenzymatic intramolecular nucleophilic substitution. The aim of this study is to determine the effect of temperature on the rate constants (k) for the activation of TREO and the hydrolysis of its epoxy derivatives in a phosphate buffer of pH 7.4 at an ionic strength of 0.16-0.17 M. Over the tested temperature range, the ln of k changed linearly with a reciprocal of absolute temperature. The mean activation energy (E) values for the TREO → S,S-EBDM and S,S-EBDM → S,S-DEB reactions were close to each other (122 and 118 kJ/mol, respectively). In opposition, the E for the hydrolysis of S,S-EBDM and S,S-DEB differed significantly (140 and 80 kJ/mol, respectively), which indicates that the structure of S,S-EBDM hampers a nucleophilic attack of water on the epoxide ring. The obtained results show that a temperature change by 1°C, from 36.5°C to 37.5°C, entails a 17% increase in the k of TREO decay, which might lead to an increased TREO clearance in vivo.
曲奥舒凡（TREO）是一种前体药物，用于治疗卵巢癌和干细胞移植前的骨髓清除性预处理。TREO 经连续激活生成单环氧中间产物（S,S-EBDM），再生成（2S,3S）-1,2:3,4-二环氧丁烷（S,S-DEB），这一过程涉及非酶促的分子内亲核取代反应。本研究旨在确定温度对 TREO 激活反应和环氧衍生物水解反应速率常数（k）的影响，所用缓冲液为 pH 7.4 的磷酸盐缓冲液，离子强度为 0.16-0.17 M。在所测试的温度范围内，ln k 与绝对温度的倒数呈线性变化。TREO→S,S-EBDM 和 S,S-EBDM→S,S-DEB 反应的平均活化能（E）值非常接近（分别为 122 和 118 kJ/mol）。相反，S,S-EBDM 和 S,S-DEB 的水解反应的 E 值差异显著（分别为 140 和 80 kJ/mol），这表明 S,S-EBDM 的结构阻碍了水分子对环氧环的亲核攻击。所得结果表明，温度从 36.5°C 升高到 37.5°C，可使 TREO 衰减的 k 值增加 17%，这可能导致体内 TREO 清除率增加。
