Evaluation of transporter-mediated hepatobiliary transport of newly developed 18F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging
Evaluation of transporter-mediated hepatobiliary transport of newly developed 18F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging
复制标题
通过 PET 成像评估新开发的 18F 标记的匹伐他汀衍生物 PTV-F1 在大鼠体内的转运蛋白介导的肝胆转运
DOI：
10.1016/j.dmpk.2019.05.006
复制
发表时间：
2019
影响因子：
2.1
通讯作者：
Saji Hideo
中科院分区：
文献类型：
--
作者：
Kimura Hiroyuki;Yagi Yusuke;Mikamo Mutsumi;Maeda Kazuya;Kagawa Shinya;Arimitsu Kenji;Higashi Tatsuya;Nishii Ryuichi;Ono Masahiro;Nakamoto Yuji;Togashi Kaori;Kusuhara Hiroyuki;Saji Hideo
需要直接在体内定量评估摄取和外排转运蛋白的功能，以了解底物药物的有效肝胆转运。匹伐他汀是有机阴离子转运多肽（OATP）和小管外排转运蛋白的底物;因此，它可以成为肝转运蛋白功能正电子发射断层扫描（PET）成像的合适探针。为了表征[F] PTV-F1（一种匹伐他汀类似物）的性能，我们通过PET成像研究了利福平（一种典型的OATP抑制剂）联合给药或Bcrp（乳腺癌耐药蛋白）敲除对大鼠[F] PTV-F1肝脏摄取和外排的影响。静脉给药后，[10 F] PTV-F1选择性蓄积在肝脏中，在PET研究期间（约40分钟），血浆、肝脏和胆汁中检测到的放射性主要来自母体PTV-F1。与利福平联合给药可使[UF] PTV-F1的肝脏摄取显著降低73%。由于其在大鼠中的清除率较低，[<$F] PTV-F1在监测肝脏OATP 1B功能变化方面比其他先前报道的OATP 1B PET探针更敏感。利福平联合给药也使放射性的胆汁排泄显著降低65%。Bcrp基因敲除对其胆汁排泄无明显影响。PTV-F1能够定量分析有机阴离子的肝胆转运系统。
Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [¹⁸F] PTV-F1, an analogue of pitavastatin, we investigated the impact of rifampicin (a typical OATP inhibitor) coadministration or Bcrp (breast cancer resistance protein) knockout on [¹⁸F] PTV-F1 hepatic uptake and efflux in rats by PET imaging. After intravenous administration,[¹⁸F] PTV-F1 selectively accumulated in the liver, and the radioactivity detected in plasma, liver, and bile mainly derived from the parent PTV-F1 during the PET study (∼ 40 min). Coadministration of rifampicin largely decreased the hepatic uptake of [¹⁸F] PTV-F1 by 73%. Because of its lower clearance in rats,[¹⁸F] PTV-F1 is more sensitive for monitoring changes in hepatic OATP1B function that other previously reported OATP1B PET probes. Rifampicin coadministration also significantly decreased the biliary excretion of radioactivity by 65%. Bcrp knockout did not show a significant impact on its biliary excretion.[¹⁸F] PTV-F1 enables quantitative analysis of the hepatobiliary transport system for organic anions.