Imatinib disposition and ABCB1 (MDR1, p-glycoprotein) genotype
Imatinib disposition and ABCB1 (MDR1, p-glycoprotein) genotype
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DOI：
10.1038/sj.clpt.6100201
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发表时间：
2007-07-01
影响因子：
6.7
通讯作者：
Schran, H.
中科院分区：
文献类型：
--
作者：
Gurney, H.;Wong, M.;Schran, H.
本研究的目的是探讨药物消除的个体差异对伊马替尼处置的影响。 22 名患有胃肠道间质瘤或慢性粒细胞白血病的患者最初接受伊马替尼 600 mg 每日治疗，随后调整毒性剂量。将第 1 天和稳态时的药代动力学参数与 CYP3A5 和 ABCB1 的消除表型和单核苷酸多态性进行比较。第 1 天，估计的伊马替尼清除率 (CL/F) 出现五倍变化，并且在稳态时平均 CL/F 下降了 26%。伊马替尼 CL/F 的降低与 ABCB1 基因型相关，在 1236T>C、2677G>T/A 和 3435C>T 基因座的胸苷纯合子中最不明显。在这些个体中，与毒性相关的剂量减少也不太常见。由于伊马替尼对消除具有明显的基因型特异性影响，ABCB1 基因型与稳态 CL/F 相关。有必要进一步评估 ABCB1 基因型和伊马替尼剂量。
The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleoticle polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.