Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Clin Cancer Res. 2011 Jan 15;17(2):294-301. doi: 10.1158/1078-0432.CCR-10-1980. Epub 2010 Nov 19.
Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).
Recently generated Slco1a/1b(-/-) (lacking all Oatp1a/1b transporters) and wild-type mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.
In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b(-/-) mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b(-/-) mice compared with wild-type. Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b(-/-) mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.
Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs.
有机阴离子转运多肽（OATP）介导广泛范围的药物的细胞摄取。疏水性抗癌药物紫杉醇（PTX）最近在体外被鉴定为 OATP1B3 的底物。我们研究了 Oatp1a/1b 转运体在体内 PTX 药代动力学中的作用，以及它们在不同剂量水平的 PTX 和甲氨蝶呤（MTX）中的影响。
最近生成的 Slco1a/1b(-/-)（缺乏所有 Oatp1a/1b 转运体）和野生型小鼠静脉注射 2、10 或 50mg/kg 的 PTX，或 10、50 或 500mg/kg 的 MTX，测量血浆和组织药物浓度。
尽管其疏水性，PTX 全身暴露（在 10mg/kg 时）在 Slco1a/1b(-/-)小鼠中比野生型增加了 2 倍以上，而 PTX 肝脏摄取减少了约 2 倍。Oatp1a/1b 转运体在广泛的剂量范围内对 PTX 和 MTX 的药代动力学有很大的影响。对于 MTX，即使在 500mg/kg 时，Oatp1a/1b 也没有达到饱和，与野生型相比，Slco1a/1b(-/-)小鼠的血浆水平增加了 3.4 倍，肝脏水平降低了 30 倍。虽然在最高剂量的 PTX 时观察到 Oatp1a/1b 的起始饱和，但 Slco1a/1b(-/-)小鼠的血浆水平仍比野生型高 1.7 倍，肝脏水平低 1.5 倍。
Oatp1a/1b 转运体在确定 MTX 和 PTX 的血浆水平和组织分布方面起着显著的作用，因此甚至影响高度疏水性的药物。由于遗传变异、抑制和/或肿瘤表达导致的 OATP1A/1B 转运体活性的变化可能会影响这些抗癌药物的毒性和治疗效果。
