Department of Clinical Pharmacy and Toxicology of the Leiden University Medical Center, Leiden, The Netherlands.
Bone Marrow Transplant. 2012 Feb;47(2):190-5. doi: 10.1038/bmt.2011.55. Epub 2011 Mar 28.
BU is used in conditioning regimens before hemopoietic SCT. High BU exposure is associated with toxicity, whereas low BU exposure leads to higher rates of therapy failure. The pharmacokinetics of BU show large interpatient variability, hypothesized to be caused by variability in BU metabolism. In this report, the effect of genetic polymorphisms in three gluthatione S-transferase genes involved in BU metabolism (hGSTA1), GSTM1 (deletion-mutation) and GSTP1 (313A/G) on the pharmacokinetics of BU in Caucasian adult patients was investigated. In all, 66 adult patients received BU as part of their conditioning regimen. After the first infusion, two serum samples were collected and measured using a HPLC assay. A one-compartment population model was used to estimate individual pharmacokinetic parameters. The genetic variants of the three glutathione S-transferase (GST) genes were determined by pyrosequencing and PCR. A reduction of 14% in BU clearance was seen for the GSTA1B allele and an increase in BU exposure was found. No relationship was found between polymorphisms in GSTM1 and GSTP1 and BU pharmacokinetics. This study shows that an increasing number of copies of GSTA1B allele results in a significant decrease of BU clearance.
BU 用于造血干细胞移植前的预处理方案。高 BU 暴露与毒性相关，而低 BU 暴露则导致治疗失败的比率更高。BU 的药代动力学显示出很大的个体间变异性，据推测这是由 BU 代谢的变异性引起的。在本报告中，研究了参与 BU 代谢的三个谷胱甘肽 S-转移酶基因（hGSTA1）、GSTM1（缺失-突变）和 GSTP1（313A/G）中的三个遗传多态性对高加索成年患者 BU 药代动力学的影响。共有 66 名成年患者接受了 BU 作为其预处理方案的一部分。第一次输注后，收集了两个血清样本并用 HPLC 测定。使用单室群体模型来估计个体药代动力学参数。通过焦磷酸测序和 PCR 确定了三种谷胱甘肽 S-转移酶 (GST) 基因的遗传变异。GSTA1B 等位基因使 BU 清除率降低了 14%，并且发现 BU 暴露增加。GSTM1 和 GSTP1 多态性与 BU 药代动力学之间没有关系。这项研究表明，GSTA1B 等位基因的拷贝数增加会导致 BU 清除率显著降低。
