Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [¹¹C]erlotinib is selectively transported by OATP2B1. In contrast to OATP1B1 and OATP1B3, OATP2B1 has not been thoroughly explored yet, and no specific probe substrates are currently available. To assess if the prototypical OATP inhibitor rifampicin can inhibit liver uptake of [¹¹C]erlotinib in vivo, we performed [¹¹C]erlotinib PET scans in six healthy volunteers without and with intravenous pretreatment with rifampicin (600 mg). In addition, FVB mice underwent [¹¹C]erlotinib PET scans without and with concurrent intravenous infusion of high-dose rifampicin (100 mg/kg). Rifampicin caused a moderate reduction in the liver distribution of [¹¹C]erlotinib in humans, while a more pronounced effect of rifampicin was observed in mice, in which rifampicin plasma concentrations were higher than in humans. In vitro uptake experiments in an OATP2B1-overexpressing cell line indicated that rifampicin inhibited OATP2B1 transport of [¹¹C]erlotinib in a concentration-dependent manner with a half-maximum inhibitory concentration of 72.0 ± 1.4 μM. Our results suggest that rifampicin-inhibitable uptake transporter(s) contributed to the liver distribution of [¹¹C]erlotinib in humans and mice and that [¹¹C]erlotinib PET in combination with rifampicin may be used to measure the activity of this/these uptake transporter(s) in vivo. Furthermore, our data suggest that a standard clinical dose of rifampicin may exert in vivo a moderate inhibitory effect on hepatic OATP2B1.

中文翻译：

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利福平对[ ¹¹ C]厄洛替尼在肝脏中分布的影响，一项在人和小鼠中进行的转化PET研究

有机阴离子转运多肽（OATP）介导各种药物从血液中摄取到肝细胞基底外侧膜中的肝脏中。正电子发射断层扫描（PET）是评估体内OATP活性的潜在强大工具，但其实用性主要取决于转运蛋白选择性探针底物的可用性。我们之前已经表明，在肝细胞中表达的三个OATP（OATP1B1，OATP1B3和OATP2B1）中，[ ¹¹ C]厄洛替尼是由OATP2B1选择性转运的。与OATP1B1和OATP1B3相比，OATP2B1尚未得到全面探索，并且目前尚无特定的探针底物。为了评估原型OATP抑制剂利福平在体内是否可以抑制[ ¹¹ C]厄洛替尼的肝吸收，我们进行了[在六名健康志愿者中进行了¹¹ C] erlotinib PET扫描，这些志愿者在未使用和使用静脉注射利福平（600 mg）的情况下进行了治疗。此外，FVB小鼠在未和同时静脉注射大剂量利福平（100 mg / kg）的情况下进行了[ ¹¹ C]厄洛替尼PET扫描。利福平会导致[ ¹¹ C]埃洛替尼在人体内的肝脏分布适度减少，而在小鼠中观察到利福平的作用更为明显，其中利福平的血浆浓度高于人。在过表达OATP2B1的细胞系中进行的体外摄取实验表明，利福平抑制了OATP2B1转运[ ^11]埃罗替尼以浓度依赖性方式存在，最大半数抑制浓度为72.0±1.4μM。我们的结果表明，利福平抑制性摄取转运蛋白促进了[ ¹¹ C]厄洛替尼在人和小鼠中的肝脏分布，并且[ ¹¹ C]厄洛替尼PET结合利福平可用于测量该/这些药物的活性。体内摄取转运蛋白。此外，我们的数据表明，标准临床剂量的利福平可能在体内对肝OATP2B1具有中等程度的抑制作用。