Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland.
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland.
Eur J Pharm Sci. 2017 Nov 15;109:616-623. doi: 10.1016/j.ejps.2017.09.011. Epub 2017 Sep 12.
For the recent years, the application of treosulfan (TREO)-based conditioning prior to hematopoietic stem cell transplantation (HSCT) has been increasing as an alternative to busulfan-based therapy, especially for patients presenting high risk of developing hepato-, pulmo-, and neurotoxicity. So far, the penetration of TREO and its epoxy-derivatives into central nervous system and aqueous humor of the eye has been investigated. However, lacking knowledge on the compounds distribution into the other key tissues precludes comprehensive understanding and assessment of TREO clinical efficacy and toxicity. In this paper, the disposition of TREO and its active monoepoxide (S,S-EBDM) in a bone marrow, liver, lungs, brain, and quadriceps femoris was studied in an animal model. Male and female adult Wistar rats (n=48/48) received an intraperitoneal injection of TREO at the dose of 500mg/kg b.w. Concentrations of TREO and S,S-EBDM in tissues were determined with a validated HPLC-MS/MS method. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis. Mean values of the maximal concentrations of TREO and S,S-EBDM in the organs were sex-independent and ranged from 61 to 1650μM and 25-105μM, respectively. No quantifiable levels of S,S-EBDM were found in the liver. Average tissue/plasma area under the curve (AUC) ratio for unbound TREO increased in the sequence: brain (0.10)<muscle (0.77)<bone marrow=lungs (0.82)<liver (0.96). The tissue/plasma AUC ratio for unbound S,S-EBDM changed as follows: brain (0.35)<lungs (0.50)<bone marrow (0.75)<muscle (1.14). Elimination half-lives of the compounds in plasma and the organs ranged from 0.7h to 2.1h. Scaling of the obtained AUCs of TREO and S,S-EBDM and the literature AUCs of busulfan to concentrations of the drugs in HSCT patients' plasma show that TREO reaches much higher levels in the organs than busulfan. Nonetheless, low S,S-EBDM exposure in a liver, lungs, and brain, even compared with busulfan, may contribute to relatively low organ toxicity of TREO-based conditioning regimens. Similarity of the scaled bone marrow AUCs of S,S-EBDM and busulfan corresponds to comparable myeloablative potency of TREO- and busulfan-based conditioning. The biological half-lives of TREO and S,S-EBDM in plasma and the studied organs indicate that 48h lag time following administration of the last dose of TREO to HSCT patients is sufficient to protect the transplanted stem cells from the compounds' exposure.
近年来，在造血干细胞移植（HSCT）前应用三嗪氟（TREO）作为替代白消安治疗的方法越来越多，尤其是对有发生肝、肺和神经毒性风险的患者。迄今为止，已经研究了 TREO 及其环氧化物衍生物渗透到中枢神经系统和眼睛房水中的情况。然而，缺乏对化合物在其他关键组织中分布的了解，妨碍了对 TREO 临床疗效和毒性的全面理解和评估。本文在动物模型中研究了 TREO 及其活性单环氧（S，S-EBDM）在骨髓、肝脏、肺、脑和股四头肌中的分布。雄性和雌性成年 Wistar 大鼠（n=48/48）以 500mg/kg bw 的剂量腹腔注射 TREO。采用经验证的 HPLC-MS/MS 方法测定组织中 TREO 和 S，S-EBDM 的浓度。在 WinNonlin 中使用非房室分析进行药代动力学计算。器官中 TREO 和 S，S-EBDM 的最大浓度的平均值与性别无关，范围分别为 61 至 1650μM 和 25-105μM。在肝脏中未发现可量化水平的 S，S-EBDM。未结合 TREO 的组织/血浆 AUC 比值按以下顺序增加：脑（0.10）<肌肉（0.77）<骨髓=肺（0.82）<肝（0.96）。未结合 S，S-EBDM 的组织/血浆 AUC 比值如下：脑（0.35）<肺（0.50）<骨髓（0.75）<肌肉（1.14）。化合物在血浆和器官中的消除半衰期范围为 0.7 至 2.1 小时。根据 HSCT 患者血浆中药物浓度对获得的 TREO 和 S，S-EBDM 的 AUC 和文献中白消安 AUC 进行标化，结果表明 TREO 在器官中的水平远高于白消安。尽管如此，肝脏、肺和脑中的 S，S-EBDM 暴露量低，甚至与白消安相比，也可能导致 TREO 为基础的调理方案的器官毒性相对较低。S，S-EBDM 和白消安的标化骨髓 AUC 相似，表明 TREO 和白消安的骨髓清除能力相似。TREO 和 S，S-EBDM 在血浆和研究器官中的生物半衰期表明，在 HSCT 患者给予 TREO 的最后一剂后 48 小时的滞后时间足以保护移植的干细胞免受化合物的暴露。
