Organic anion transporter (OAT) 2 and OAT7 were recently shown to be involved in the hepatic uptake of drugs; however, there is limited understanding of the population variability in the expression of these transporters in liver. There is also a need to derive relative expression-based scaling factors (REFs) that can be used to bridge in vitro functional data to the in vivo drug disposition. To this end, we quantified OAT2 and OAT7 surrogate peptide abundance in a large number of human liver tissue samples (n = 52), as well as several single-donor cryopreserved human hepatocyte lots (n = 30) by a novel, validated liquid chromatography tandem mass spectrometry (LC–MS/MS) method. The average surrogate peptide expression of OAT2 and OAT7 in the liver samples was 1.52 ± 0.57 and 4.63 ± 1.58 fmol/μg membrane protein, respectively. While we noted statistically significant differences (p < 0.05) in hepatocyte and liver tissue abundances for both OAT2 and OAT7, the differences were relatively small (1.8- and 1.5-fold difference in median values, respectively). Large interindividual variability was noted in the hepatic expression of OAT2 (16-fold in liver tissue and 23-fold in hepatocytes). OAT7, on the other hand, showed less interindividual variability (4-fold) in the livers, but high variability for the hepatocyte lots (27-fold). A significant positive correlation in OAT2 and OAT7 expression was observed, but expression levels were neither associated with age nor sex. In conclusion, our data suggest marked interindividual variability in the hepatic expression of OAT2/7, which may contribute to the pharmacokinetic variability of their substrates. Because both transporters were less abundant in hepatocytes than livers, a REF-based approach is recommended when scaling in vitro hepatocyte transport data to predict hepatic drug clearance and liver exposure of OAT2/7 substrates.

中文翻译：

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定量人类肝脏组织和原代肝细胞中肝有机阴离子转运蛋白OAT2和OAT7

最近显示有机阴离子转运蛋白（OAT）2和OAT7参与肝对药物的吸收；其中，有机负离子转运蛋白（OAT）2和OAT7参与肝吸收。但是，对这些转运蛋白在肝脏中表达的种群变异性的了解有限。还需要获得基于相对表达的比例因子（REF），其可用于将体外功能数据桥接至体内药物配置。为此，我们对大量人肝组织样品（n = 52）以及几个单供体冷冻保存的人肝细胞批次（n= 30）通过一种新颖的，经过验证的液相色谱串联质谱分析（LC-MS / MS）方法。肝样品中OAT2和OAT7的平均替代肽表达分别为1.52±0.57和4.63±1.58 fmol /μg膜蛋白。尽管我们注意到了统计学上的显着差异（pOAT2和OAT7在肝细胞和肝组织丰度中的<0.05）差异相对较小（中位数差异分别为1.8倍和1.5倍）。OAT2在肝中的表达存在较大的个体差异（肝组织中为16倍，肝细胞中为23倍）。另一方面，OAT7在肝脏中的个体变异性较小（4倍），但肝细胞批次的变异性较高（27倍）。观察到OAT2和OAT7表达的显着正相关，但表达水平与年龄和性别均无关。总之，我们的数据表明OAT2 / 7在肝表达中存在明显的个体差异，这可能有助于其底物的药代动力学变异。由于这两种转运蛋白的肝细胞含量都不如肝脏丰富，