Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.
Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.
复制标题
GST 多态性对日本儿童白消安药代动力学的影响。
DOI：
10.1111/ped.13859
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Kawano Y.
中科院分区：
文献类型：
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作者：
Nishikawa T;Yamaguchi H;Ikawa K;Nakayama K;Higashi E;Miyahara E;Abematsu T;Nakagawa S;Kodama Y;Tanabe T;Shigemi A;Shinkoda Y;Okamoto Y;Takeda Y;Kawano Y.
背景在造血干细胞移植中，白消安暴露过量或不足均可引起致命的不良反应或复发。鉴于白消安主要通过谷胱甘肽S-转移酶（GST）代谢，我们研究了GST多态性对日本儿科患者白消安药代动力学的影响。使用高效液相色谱法测量血浆白消安浓度。计算血浆白消安浓度-时间曲线下面积（AUC）。采用聚合酶链反应-限制性片段长度多态性技术检测GSTA 1基因型。采用多重PCR方法检测GSTM 1和GSTT 1基因的存在与否。表型预测定义如下：弱代谢型（n= 4），一种或多种GSTA 1 * B单倍型或GSTM 1/GSTT 1双无效基因型;强代谢型（n= 16），其他基因型。GSTA 1、M1和T1在AUC 0-∞、清除率或消除速率常数方面独立无显著差异。对于AUC 0-∞意外升高（2，591 μmol/L min）的婴儿，GSTA 1、M1和T1多态性为野生型。除上述患者外，慢代谢组清除率低于快代谢组（1，531 vs 1，010 μmol/L min;P< 0.01），AUC 0-∞高于快代谢组（1，531 vs 1，010 μmol/L min;P< 0.01）。结论GST基因多态性可能影响白消安的药代动力学，但这些影响被其他因素掩盖，如基础疾病、全身状况、治疗史和种族。
BackgroundFatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathioneS‐transferase (GST), we investigated the influence ofGSTpolymorphisms on busulfan pharmacokinetics in Japanese pediatric patients.MethodsBlood samples were taken from patients receiving high‐dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high‐performance liquid chromatography. The area under the plasma busulfan concentration–time curve (AUC) was calculated. The genotype ofGSTA1was determined on polymerase chain reaction (PCR)‐restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence ofGSTM1andGSTT1in the genomic DNA samples.ResultsTwenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n= 4), one or moreGSTA1*Bhaplotype orGSTM1/GSTT1double‐null genotypes; and extensive metabolizer (n= 16), other genotypes.GSTA1,M1, andT1independently had no significant differences in AUC0‐∞, clearance or elimination rate constant. For the infant with unexpectedly high AUC0‐∞(2,591 μmol/L min), theGSTA1,M1,andT1polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0‐∞,except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 μmol/L min;P< 0.01).ConclusionsGSTpolymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.