Myers Alan L, Kawedia Jitesh D, Champlin Richard E, Kramer Mark A, Nieto Yago, Ghose Romi, Andersson Borje S
a Department of Pharmacy Research, Division of Pharmacy , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
b Department of Stem Cell Transplantation , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA.
Expert Opin Drug Metab Toxicol. 2017 Sep;13(9):901-923. doi: 10.1080/17425255.2017.1360277. Epub 2017 Aug 17.
Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.
白消安（Bu）是一种治疗窗有限的烷化剂，在药代动力学（PK）方面存在患者间差异。尽管已使用数十年，但基于白消安PK的药物相互作用（DDI）机制以及这些DDI的负面下游效应尚未完全明确。涵盖领域：本文概述了白消安的PK，主要关注已知和潜在未知的药物代谢途径如何影响与白消安相关的DDI。此外，总结了在干细胞移植诊所（SCT）中观察到的白消安化疗的药物基因组学和与白消安相关的DDI。最后强调了白消安治疗药物监测日益增加的重要性。专家观点：白消安代谢的机制研究表明，除谷胱甘肽S-转移酶（GST）同工酶外，其他氧化酶（细胞色素P450酶、黄素单加氧酶）和ABC/MDR药物转运蛋白可能对白消安的总体清除有贡献。尽管有许多见解，但临床研究结果，尤其是在联合用药情况下以及儿科和成人患者之间的结果，仍然相互矛盾。需要进一步开展基础科学和临床研究工作，以充分了解决定白消安PK特征及其对SCT后并发症影响的关键因素。改进的治疗药物监测策略是在高度复杂的SCT治疗环境中进一步研究例如DDI机制和患者预后的有前景的组成部分。
