Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
复制标题
肝脏有机阴离子传输多肽对多西秒摄取和清除的贡献。
DOI：
10.1158/1535-7163.mct-14-0547
复制
发表时间：
2015-04
影响因子：
5.7
通讯作者：
Ho RH
中科院分区：
文献类型：
--
作者：
Lee HH;Leake BF;Teft W;Tirona RG;Kim RB;Ho RH
抗微管药物多西他赛是一种广泛用于治疗多种实体瘤的化疗药物，主要依赖于肝脏处置。在这项研究中，我们评估了能够转运放射性标记的多西他赛的药物摄取转运蛋白。通过使用基于重组牛痘的方法筛选HeLa细胞中的药物摄取转运蛋白阵列，鉴定了5种能够摄取多西他赛的有机阴离子转运多肽（OATP）：OATP 1A 2、OATP 1B 1、OATP 1B 3、OATP 1C 1和Oatp 1b 2。多西他赛转运的动力学分析显示，肝脏OATP 1B/1b转运蛋白的动力学参数相似。SLCO 1B 1和SLCO 1B 3多态性（SNP）评估显示，许多OATP 1B 1和OATP 1B 3变体与多西他赛转运受损相关。使用MDCKII稳定细胞进行的基于transwell的载体转运试验显示，与单转染（MDCKII-OATP 1B 1和MDCKII-OATP 1B 3）细胞（p<0.05）或对照（MDCKII-Co）细胞（p <0.001）相比，多西他赛显著转运至双转染（MDCKII-OATP 1B 1/MDR 1和MDCKII-OATP 1B 3/MDR 1）细胞的顶室。在Slco 1b 2 −/−小鼠中进行的多西他赛体内转运研究显示，与野生型小鼠相比，多西他赛的血浆浓度高约5.5倍（p<0.01），肝脏/血浆比降低约3倍（p<0.05）。Slco 1b 2 −/−小鼠中多西他赛的血浆清除率比野生型小鼠低83%（p<0.05）。总之，本研究证明了OATP 1B转运蛋白对多西他赛肝脏分布和清除的重要作用，以及这些转运蛋白对多西他赛药代动力学的支持作用。
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion transporting polypeptides (OATPs) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double transfected-(MDCKIIOATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared to single transfected-(MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (p<0.05) or control (MDCKII-Co) cells (p<0.001). In vivo docetaxel transport studies in Slco1b2−/− mice showed ~>5.5-fold higher plasma concentrations (p<0.01) and ~3-fold decreased liver-to-plasma ratio (p<0.05) of docetaxel compared to wild-type mice. The plasma clearance of docetaxel in Slco1b2−/− mice was 83% lower than wild-type mice (p<0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.