Department of Radiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (P.B., F.C., C.M.P.); and Laboratory of Imaging Biomarkers, Centre of Research on Inflammation, Unité Mixte de Recherche 1149, Institut National de la santé et de la Recherche Médicale and University Paris Diderot, Paris, France (C.M.P.).
Department of Radiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (P.B., F.C., C.M.P.); and Laboratory of Imaging Biomarkers, Centre of Research on Inflammation, Unité Mixte de Recherche 1149, Institut National de la santé et de la Recherche Médicale and University Paris Diderot, Paris, France (C.M.P.)
Drug Metab Dispos. 2019 Apr;47(4):412-418. doi: 10.1124/dmd.118.084624. Epub 2019 Jan 23.
In the liver, several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. These approaches include in vitro assays and pharmacokinetic models that predict how inhibitors modify the systemic and liver concentrations of the victim drugs. Imaging is another approach that shows how inhibitors might alter liver concentrations stronger than systemic concentrations. In perfused rat livers associated with a gamma counter that measures liver concentrations continuously, we previously showed how fluxes across transporters generate the hepatocyte concentrations of two clinical imaging compounds, one with a low extraction ratio [gadobenate dimeglumine (BOPTA)] and one with a high extraction ratio [mebrofenin (MEB)]. BOPTA and MEB are transported by rat organic anion transporting polypeptide and multiple resistance-associated protein 2, which are both inhibited by rifampicin. The aim of the study is to measure how rifampicin modifies the hepatocyte concentrations and membrane clearances of BOPTA and MEB and to determine whether these compounds might be used to investigate transporter-mediated drug-drug interactions in clinical studies. We show that rifampicin coperfusion greatly decreases BOPTA hepatocyte concentrations, but increases those of MEB. Rifampicin strongly decreases BOPTA hepatic clearance. In contrast, rifampicin decreases moderately MEB hepatic clearance and blocks the biliary intrinsic clearance, increasing MEB hepatocyte concentrations. In conclusion, low concentrations prevent the quantification of BOPTA biliary intrinsic clearance, while MEB is a promising imaging probe substrate to evidence transporter-mediated drug-drug interactions when inhibitors act on influx and efflux transporters.
在肝脏中，人们采用了几种方法来研究和预测药物诱导转运体抑制这一复杂问题。这些方法包括体外检测和药代动力学模型，它们可以预测抑制剂如何改变受影响药物的全身和肝脏浓度。成像则是另一种方法，它可以显示抑制剂如何改变肝脏浓度，使其比全身浓度改变更明显。在与γ计数器相连的灌注大鼠肝脏中，我们可以连续测量肝脏浓度，此前我们已经展示了转运体如何产生两种临床成像化合物的肝细胞浓度，一种化合物的提取率低[钆贝葡胺（BOPTA）]，另一种化合物的提取率高[美罗培南（MEB）]。BOPTA 和 MEB 由大鼠有机阴离子转运多肽和多药耐药相关蛋白 2 转运，这两种蛋白均被利福平抑制。本研究的目的是测量利福平如何改变 BOPTA 和 MEB 的肝细胞浓度和膜清除率，并确定这些化合物是否可用于在临床研究中调查转运体介导的药物相互作用。我们发现，利福平共灌注大大降低了 BOPTA 的肝细胞浓度，但增加了 MEB 的肝细胞浓度。利福平强烈降低了 BOPTA 的肝清除率。相反，利福平适度降低了 MEB 的肝清除率，并阻断了 MEB 的胆内清除率，增加了 MEB 的肝细胞浓度。总之，低浓度会妨碍对 BOPTA 胆内清除率的定量，而 MEB 是一种有前途的成像探针底物，可在抑制剂作用于流入和流出转运体时证明转运体介导的药物相互作用。
