Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese:: roles of UGT1A1*6 and*28
Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese:: roles of UGT1A1*6 and*28
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DOI：
10.1097/fpc.0b013e328014341f
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发表时间：
2007-07-01
影响因子：
2.6
通讯作者：
Saijo, Nagahiro
中科院分区：
文献类型：
--
作者：
Minami, Hironobu;Sai, Kimie;Saijo, Nagahiro
SN-38是伊立替康的一种活性代谢物，可通过UGT1A亚型1A1、1A7、1A9和1A10的糖醛酸化解毒。UGT1A单倍型覆盖所有这些亚型的药物遗传学信息对于伊立替康的个体化治疗具有重要意义。研究UGT1A单倍型与伊立替康药代动力学/药效学之间的关系，以确定药物遗传标记。方法分析伊立替康单用或联合化疗的177例日本肿瘤患者UGT1A单倍型与浓度曲线下面积比（SN-38葡糖苷/SN-38）或毒性的关系。为了进行关联分析，使用了UGT1A基因片段[（1A1, 1A7, 1A9, 1A10）和C块（共同外显子2-5）]的二倍型和组合单倍型（1A9-1A7-1A1）。研究了55例单独使用伊立替康治疗的患者双倍型与毒性的关系。结果在UGT1A基因的二倍型中，携带UGT1A1*6或*28的单倍型患者的浓度曲线比下面积明显减小，UGT1A1*6或*28的影响程度相似。含有*28或*6的单倍型数量对浓度曲线比下面积存在基因剂量效应（0、1和2个单倍型分别为5.55、3.62和2.07,P < 0.0001）。多因素分析发现53例伊立替康单药治疗患者中*6和*28纯合子和双杂合子（*6/*6、*28/*28和*6/*28）与严重中性粒细胞减少症显著相关。结论与浓度曲线下面积比减小和中性粒细胞减少显著相关的单倍型含有UGT1A1*6或*28，在伊立替康应用于日本和其他亚洲患者之前，应对这两种单倍型进行基因分型。
Objectives SN-38, an active metabolite of irinotecan, is detoxified by glucuronidation with UGT1A isoforms, 1A1, 1A7, 1A9, and 1A10. The pharmacogenetic information on UGT1A haplotypes covering all these isoforms is important for the individualized therapy of irinotecan. Associations between UGT1A haplotypes and pharmacokinetics/pharmacodynamics of irinotecan were investigated to identify pharmacogenetic markers.Methods Associations between UGT1A haplotypes and the area under concentration curve ratio (SN-38 glucuronide/SN-38) or toxicities were analyzed in 177 Japanese cancer patients treated with irinotecan as a single agent or in combination chemotherapy. For association analysis, diplotypes of UGT1A gene segments [(1A1, 1A7, 1A9, 1A10), and Block C (common exons 2-5)] and combinatorial haplotypes (1A9-1A7-1A1) were used. The relationship between diplotypes and toxicities was investigated in 55 patients treated with irinotecan as a single agent.Results Among diplotypes of UGT1A genes, patients with the haplotypes harboring UGT1A1*6 or *28 had significantly reduced area under concentration curve ratios, with the effects of UGT1A1*6 or *28 being of a similar scale. A gene dose effect on the area under concentration curve ratio was observed for the number of haplotypes containing *28 or *6 (5.55, 3.62, and 2.07 for 0, 1, and 2 haplotypes, respectively, P < 0.0001). In multivariate analysis, the homozygotes and double heterozygotes of *6 and *28 (*6/*6, *28/*28 and *6/*28) were significantly associated with severe neutropenia in 53 patients who received irinotecan monotherapy.Conclusions The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.