Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Sci Rep. 2017 May 10;7(1):1711. doi: 10.1038/s41598-017-01861-7.
Owing to its narrow therapeutic range and high pharmacokinetic variability, optimal dosing for busulfan is important to minimise overexposure-related systemic toxicity and underexposure-related graft failure. Using global metabolomics, we investigated biomarkers for predicting busulfan exposure. We analysed urine samples obtained before busulfan administration from 59 paediatric patients divided into 3 groups classified by area under the busulfan concentration-time curve (AUC), i.e., low-, medium-, and high-AUC groups. In the high-AUC group, deferoxamine metabolites were detected. Phenylacetylglutamine and two acylcarnitines were significantly lower in the high-AUC group than in the low-AUC group. Deferoxamine, an iron-chelating agent that lowers serum ferritin levels, was detected in the high-AUC group, indicating that those patients had high ferritin levels. Therefore, in a retrospective study of 130 paediatric patients, we confirmed our hypothesis that busulfan clearance (dose/AUC) and serum ferritin level has a negative correlation (r = -0.205, P = 0.019). Ferritin, acylcarnitine, and phenylacetylglutamine are associated with liver damage, including free radical formation, deregulation of hepatic mitochondrial β-oxidation, and hyperammonaemia. Our findings reveal potential biomarkers predictive of busulfan exposure and suggest that liver function may affect busulfan exposure.
由于其治疗范围狭窄和药代动力学变异性高，为了将与过度暴露相关的全身毒性和与暴露不足相关的移植物失败降到最低，布美他尼的最佳剂量非常重要。我们使用全局代谢组学研究了预测布美他尼暴露的生物标志物。我们分析了 59 名儿科患者在给予布美他尼之前获得的尿液样本，这些患者分为 AUC（布美他尼浓度-时间曲线下面积）低、中、高 3 组。在高 AUC 组中，检测到去铁胺代谢物。与低 AUC 组相比，高 AUC 组中的苯乙酰谷氨酰胺和两种酰基辅酶 A 显著降低。去铁胺是一种降低血清铁蛋白水平的铁螯合剂，在高 AUC 组中检测到，表明这些患者的铁蛋白水平较高。因此，在对 130 名儿科患者的回顾性研究中，我们证实了我们的假设，即布美他尼清除率（剂量/AUC）和血清铁蛋白水平呈负相关（r=-0.205，P=0.019）。铁蛋白、酰基辅酶 A 和苯乙酰谷氨酰胺与肝损伤有关，包括自由基形成、肝线粒体β-氧化失调和高氨血症。我们的研究结果揭示了预测布美他尼暴露的潜在生物标志物，并表明肝功能可能会影响布美他尼的暴露。
