Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity.
Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity.
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DOI：
10.1038/psp.2014.23
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发表时间：
2014-07-23
影响因子：
3.5
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
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作者：
Yamada, A;Maeda, K;Kiyotani, K;Mushiroda, T;Nakamura, Y;Sugiyama, Y
中性粒细胞减少症是多西紫杉醇致死性剂量限制性毒性。我们之前的报告表明，多西他赛诱导的严重中性粒细胞减少症的流行与溶质载体有机阴离子转运蛋白1B3 (SLCO1B3)（编码有机阴离子转运多肽1B3 (OATP1B3)）和atp结合盒亚家族C2 (ABCC2)（编码多药耐药相关蛋白2 (MRP2)）的遗传多态性显著相关。因此，我们研究了它们在多西他赛诱导的中性粒细胞减少症中的意义。体外实验表明它们可能参与多西紫杉醇的肝脏摄取和骨髓细胞的外排。为了进一步表征OATP1B3和MRP2对中性粒细胞减少症的定量影响，我们在药代动力学/药理学模型中对多西他赛治疗后OATP1B3和MRP2功能改变的受试者的中性粒细胞计数进行了计算机模拟。临床报道的多西他赛诱导的中性粒细胞减少风险的优势比可以用OATP1B3和MRP2功能下降分别为41%和32%来解释。这些结果表明，OATP1B3和MRP2活性的降低分别与骨髓细胞的全身暴露和局部积累有关，这是临床上观察到的多西他赛诱导中性粒细胞减少的原因。
Neutropenia is a lethal dose-limiting toxicity of docetaxel. Our previous report indicated that the prevalence of severe docetaxel-induced neutropenia is significantly associated with genetic polymorphisms in solute carrier organic anion transporter 1B3 (SLCO1B3) (encoding organic anion–transporting polypeptide 1B3 (OATP1B3)) and ATP-binding cassette subfamily C2 (ABCC2) (encoding multidrug-resistant–associated protein 2 (MRP2)). Therefore, we investigated their significance in docetaxel-induced neutropenia. In vitro experiments suggested their possible involvement in the hepatic uptake of docetaxel and its efflux from bone marrow cells. To further characterize a quantitative impact of OATP1B3 and MRP2 on neutropenia, we used an in silico simulation of the neutrophil count in docetaxel-treated subjects with functional changes in OATP1B3 and MRP2 in a pharmacokinetic/pharmacodynamic model. The clinically reported odds ratios for docetaxel-induced neutropenia risk were explained by the decreased function of OATP1B3 and MRP2 to 41 and 32%, respectively. These results suggest that reduced activities of OATP1B3 and MRP2 associated with systemic exposure and local accumulation in bone marrow cells, respectively, account for the docetaxel-induced neutropenia observed clinically.