Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation
Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation
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DOI：
10.1016/j.bbmt.2010.12.708
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发表时间：
2011-08-01
影响因子：
4.3
通讯作者：
Lee, Kyoo-Hyung
中科院分区：
文献类型：
--
作者：
Kim, Sung-Doo;Lee, Je-Hwan;Lee, Kyoo-Hyung
与口服制剂相比，静脉注射（i.v.）布苏凡可以产生更一致的药代动力学特征，但尽管如此，显著的患者间差异是显而易见的。我们研究了3个GST同工酶基因（GSTA1、GSTM1和GSTT1）的多态性对静脉注射布硫凡清除的影响。本研究纳入了58例接受3.2 mg/kg/天布苏凡作为造血细胞移植调节的成年患者。逐步多元线性回归结果显示，GSTA1变异型GSTA1*B （P = 0.004）、GSTM1/GSTT1双零基因型（P = 0.039）和实际体重（P = 0.001）与静脉注射布磺胺清除率降低显著相关。结合GSTA I基因多态性和GSTM1-和GSTT-null基因型数量，分析GST基因型对布苏凡药代动力学总体影响的趋势检验显示，GST基因型与布苏凡清除率之间存在显著相关性（P = .001）。GSTA1*A/*A和GSTM1/GSTT1双阴性基因型患者与GSTA1*A/*B和GSTM1/GSTT1双阳性基因型患者静脉注射布苏凡的清除率相似。综上所述，利用GST基因多态性的药物遗传学方法可能对优化布硫凡静脉给药方案有价值。我们的研究结果还强调了在药物遗传学研究中包括多基因分析和解决同工酶基因之间相互作用的重要性。血液与骨髓移植[j] .中华医学杂志，2011,(2):1 - 4
Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes (GSTA1, GSTM1, and GSTT1) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1*B (P = .004), GSTM1/GSTT1 double-null genotype (P = .039), and actual body weight (P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA I gene polymorphism and the number of GSTM1- and GSTT-null genotypes, showed a significant correlation between GST genotype and busulfan clearance (P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1*A/*A and GSTM1/GSTT1 double-null genotypes and those with GSTA1*A/*B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies. Biol Blood Marrow Transplant 17: 1222-1230 (2011) (C) 2011 American Society for Blood and Marrow Transplantation