Influence of glutathione S-transferase A1 polymorphism on the phartnacokinetics of busulfan
Influence of glutathione S-transferase A1 polymorphism on the phartnacokinetics of busulfan
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DOI：
10.1016/j.cca.2005.12.011
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发表时间：
2006-06-01
影响因子：
5
通讯作者：
Iga, TatsuJi
中科院分区：
文献类型：
--
作者：
Kusama, Makiko;Kubota, Takahiro;Iga, TatsuJi
背景：大剂量口服白消安用于造血干细胞移植前的清髓性化疗。过量或不足的白消安暴露可能会发生致命的不良反应或复发。谷胱甘肽S-转移酶（GST）A1，其启动子区的遗传多态性已被报道，负责白消安代谢。我们调查了GSTA 1的多态性白消安的药代动力学。方法：血液样本（6或7点）从接受高剂量口服白消安（约1毫克/公斤，每6小时）剂量1和5的患者。结果：12例患者入选本研究。9例患者的基因分型为野生型（GSTA 1 *A/*A），3例为杂合变异型（GSTA 1 *A/*B）。在第5次给药时，杂合子组的消除常数显著较低（0.176 +/- 0.038 vs. 0.315 +/- 0.021 h-1; P=0.008）和经生物利用度校正的清除率（0.118 +/- 0.013 vs. 0.196 +/- 0.011 1/h/kg; P=0.004），平均血浆白消安浓度显著升高（1344 +/- 158 vs.854 +/- 44 ng/ml; P=0.001）。结论：这是首次报道GSTA 1多态性对白消安消除的显著影响。这可能是白消安药代动力学个体间差异较大的原因，随着更多信息证实我们的研究，白消安高剂量治疗可能提前通过GSTA 1基因分型进行优化。(c)2005 Elsevier B.V保留所有权利。
Background: High-dose oral busulfan is used for myeloablative chemotherapy before hematopoietic stein-cell transplantation. Fatal adverse effects or relapse may occur with excess or insufficient busulfan exposure. Glutathione S-transferase (GST) A1, whose genetic polymorphism in its promoter region has been reported, is responsible for busulfan metabolism. We investigated the polymorphism of GSTA1 on busulfan pharmacokinetics.Methods: Blood samples (6 or 7 points) were taken from patients receiving high-dose oral busulfan (approximately 1 mg/kg every 6 h) on Doses 1 and 5. Pharmacokinetic parameters were calculated from plasma busulfan concentration.Results: Twelve patients were enrolled in this study. Nine patients were genotyped as wildtype (GSTA1*A/*A), and 3 as heterozygous variants (GSTA1*A/*B). At Dose 5, the heterozygous group had significantly lower elimination constant(0.176 +/- 0.038 vs. 0.315 +/- 0.021 h-1; P=0.008) and clearance corrected by bioavailability (0.118 +/- 0.013 vs. 0.196 +/- 0.011 1/h/kg; P=0.004), and significantly higher mean plasma busulfan concentration (1344 +/- 158 vs. 854 +/- 44 ng/ml; P=0.001) than the wildtype.Conclusions: This is the first report on the significant influence of GSTA1 polymorphism on busulfan elimination. This may account for the large inter-individual variance in busulfan pharmacokinetics, and with more information confirming our study, busulfan high-dose therapy may be optimized by GSTA1 genotyping in advance. (c) 2005 Elsevier B.V All rights reserved.