大剂量甲氨蝶呤在小儿急性淋巴细胞白血病:ABCC2多态性对等离子体浓度的影响。

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劳T, B Erney戈尔R, Eschenhagen T,贝克J,兰格T

大剂量甲氨蝶呤在小儿急性淋巴细胞白血病:ABCC2多态性对等离子体浓度的影响。

中国新药杂志。2006年11月,80 (5):468 - 76。

PubMed ID

17112803 (在PubMed

]

文摘

目的:腺苷triphosphate-binding磁带(ABC)类运输车ABCC2 (MRP2[多药耐药性相关蛋白2]或cMOAT(微管的multispecific有机阴离子转运体])参与细胞向外运输和消除甲氨蝶呤。我们假设常见基因变异可能导致大剂量甲氨蝶呤药物动力学的变化。方法:ABCC2的所有32个外显子基因的多态性分析的参照组59健康白色主题通过聚合酶链反应,单链构象多态性和测序。随后,我们评估了协会的多态性与甲氨蝶呤血浆浓度在44岁小儿急性淋巴细胞白血病(ALL)患者(29岁男性和15个女性患者;平均年龄6.8 + / - -4.8年)。患者接受4周期5000 mg / m2的身体表面积根据ALL-Berlin-Frankfurt-Muenster (BFM) 95或2000 ALL-BFM协议。参照组的结果:我们发现8频繁的单核苷酸多态性。五个完整的连锁不平衡。总的来说,5新多态性描述。病人群体的基因型分布没有明显不同于集体的引用。 The mean plasma methotrexate area under the curve from 36 to 48 hours after the start of the infusion was significantly 2-fold higher in female patients carrying at least 1 -24T allele as compared with all other patients (14.2+/-12.8 h.micromol/L versus 6.9+/-4.2 h.micromol/L, P<.001). The risk to have 2 or more cycles necessitating an intensification of folinate rescue was 9-fold (95% confidence interval, 1.8- to 44-fold) in female patients carrying at least 1 T allele (P=.0067). CONCLUSION: The data suggest a hitherto unknown gender-specific impact of the -24C>T ABCC2 gene polymorphism on high-dose methotrexate pharmacokinetics. Whereas a nonfunctional MRP2 variant has been described in a patient with severe impairment of methotrexate excretion, our study is the first to suggest that a frequent ABCC2 polymorphism contributes to variability of methotrexate kinetics.

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药物靶点

药物	目标	类	生物	药理作用	行动
三磷酸腺苷	微管的multispecific有机阴离子转运体1	蛋白质	人类	未知的	不可用	细节