Romański Michał, Baumgart Joachim, Böhm Sonja, Główka Franciszek K
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.).
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.)
Drug Metab Dispos. 2015 Dec;43(12):1946-54. doi: 10.1124/dmd.115.066050. Epub 2015 Oct 1.
Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into the CNS was studied in juvenile (JR) and young adult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S,S-EBDM, and S,S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREO was 0.14, 0.17, 0.10, and 0.07 and for unbound S,S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S,S-EBDM, respectively. Elimination rate constants of TREO and S,S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S,S-DEB were found in the studied samples. TREO and S,S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO-related CNS exposure than young adults.
曲奥舒凡（TREO）目前正作为造血干细胞移植预处理中白消安的替代治疗方法进行研究。关于该药物血脑屏障穿透性的了解仍然很少。本文首次在幼年（JR）和年轻成年大鼠（YAR）中研究了TREO及其活性单环氧化物（S,S-EBDM）和双环氧化物（S,S-DEB）进入中枢神经系统的情况。两种性别的CD大鼠（n = 96）静脉注射剂量为500 mg/kg体重的TREO。通过经过验证的生物分析方法测定大鼠血浆、脑和脑脊液（仅在YAR中）中TREO、S,S-EBDM和S,S-DEB的浓度。在WinNonlin中使用非房室分析进行药代动力学计算，并在Statistica软件中进行统计评估。在雄性JR、雌性JR、雄性YAR和雌性YAR中，游离TREO的脑/血浆曲线下面积（AUC）比值分别为0.14、0.17、0.10和0.07，游离S,S-EBDM的该比值分别为0.52、0.48、0.28和0.22。在雄性和雌性YAR中，TREO的脑脊液/血浆AUC比值分别为0.12和0.11，S,S-EBDM的该比值分别为0.66和0.64。所有基质中TREO和S,S-EBDM的消除速率常数与性别无关，且在JR中有降低的趋势。在所研究的样本中未发现可量化水平的S,S-DEB。TREO和S,S-EBDM进入中枢神经系统的穿透性较差且与性别无关。然而，幼年大鼠的脑暴露量更大，因此非常年幼的儿童可能比年轻成年人更容易受到高剂量TREO相关中枢神经系统暴露的影响。
