Marie Solène, Hernández-Lozano Irene, Breuil Louise, Saba Wadad, Novell Anthony, Gennisson Jean-Luc, Langer Oliver, Truillet Charles, Tournier Nicolas
Université Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Frédéric Joliot, 4 place du Général Leclerc, 91401 Orsay, France.
Département de Pharmacie Clinique, Faculté de Pharmacie, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
Pharmaceutics. 2020 May 27;12(6):486. doi: 10.3390/pharmaceutics12060486.
The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [Tc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [Tc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats ( = 5-6 per group) to assess the kinetics of [Tc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound ( = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [Tc]mebrofenin from the liver to the bile (). Higher doses of DTZ and CsA did not further decrease but dose-dependently decreased the uptake () and backflux () rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [Tc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.
多药耐药相关蛋白2（MRP2）介导药物和代谢物的胆汁排泄。[锝]美罗芬宁可作为肝脏MRP2活性的探针，因为其胆汁排泄主要由该转运蛋白介导。由于[锝]美罗芬宁的肝脏摄取取决于有机阴离子转运多肽（OATP）活性，因此需要一种安全的方案来靶向抑制肝脏MRP2，以研究每个转运系统的内在作用。地尔硫䓬（DTZ）和环孢素A（CsA）首先在体外被证实是有效的MRP2抑制剂。对大鼠（每组5 - 6只）进行动态采集，以评估增加抑制剂剂量后[锝]美罗芬宁在肝脏、肠道和心脏血池中的动力学。使用多普勒超声评估它们对肝血流的影响（每组4只）。DTZ（皮下注射，10 mg/kg）和低剂量CsA（静脉注射，0.01 mg/kg）选择性地降低了[锝]美罗芬宁从肝脏向胆汁的转运（）。更高剂量的DTZ和CsA并没有进一步降低，但剂量依赖性地降低了血液与肝脏之间的摄取（）和回流（）速率常数。高剂量的DTZ（静脉注射，3 mg/kg）而不是CsA（静脉注射，5 mg/kg）显著降低了门静脉和肝动脉的血流。在不影响OATP活性和肝血流的情况下，可以在体内实现对肝脏MRP2活性的靶向药理抑制。有必要进行临床研究，以验证[锝]美罗芬宁与低剂量CsA联合作为一种新型底物/抑制剂对，以阐明OATP和MRP2活性在肝脏疾病中的作用。
