Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Clin Pharmacol Ther. 2011 Jul;90(1):157-63. doi: 10.1038/clpt.2011.102. Epub 2011 Jun 1.
The purpose of this study was to explore the role of the organic anion-transporting polypeptide (OATP) 1A2, which is encoded by SLCO1A2, in the cellular uptake of the Bcr-Abl tyrosine kinase inhibitor imatinib, and the relationship between SLCO1A2 polymorphisms and the pharmacokinetics of imatinib in patients with chronic myeloid leukemia (CML). Imatinib uptake was significantly enhanced in OATP1A2-transfected human embryonic kidney (HEK) 293 cells (P = 0.002). Naringin, an OATP1A2 inhibitor, decreased the transport of imatinib in OATP1A2-transfected HEK293 cells, the human intestinal cell line Caco-2, and K562 CML cells. Linkage disequilibrium was found between the SLCO1A2 -1105G>A and -1032G>A genotypes in 34 CML patients and 100 healthy subjects. Imatinib clearance in CML patients was influenced by the SLCO1A2 -1105G>A/-1032G>A genotype (P = 0.075) and the SLCO1A2 -361GG genotype (P = 0.005). These findings suggest that imatinib is transported into cells by OATP1A2, and that SLCO1A2 polymorphisms significantly affect imatinib pharmacokinetics.
本研究旨在探讨有机阴离子转运多肽 1A2（OATP1A2）在细胞摄取 Bcr-Abl 酪氨酸激酶抑制剂伊马替尼中的作用，以及 SLCO1A2 多态性与慢性髓系白血病（CML）患者伊马替尼药代动力学的关系。OATP1A2 转染的人胚肾（HEK）293 细胞中伊马替尼摄取明显增强（P=0.002）。柚皮苷是 OATP1A2 的抑制剂，可降低 OATP1A2 转染的 HEK293 细胞、人肠细胞系 Caco-2 和 K562 CML 细胞中伊马替尼的转运。在 34 例 CML 患者和 100 例健康对照者中发现 SLCO1A2-1105G>A 和-1032G>A 基因型之间存在连锁不平衡。CML 患者的伊马替尼清除率受 SLCO1A2-1105G>A/-1032G>A 基因型（P=0.075）和 SLCO1A2-361GG 基因型（P=0.005）的影响。这些发现表明伊马替尼通过 OATP1A2 进入细胞，SLCO1A2 多态性显著影响伊马替尼的药代动力学。
