The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [^99mTc]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 [^99mTc]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 (n = 5–6 per group) to assess the kinetics of [^99mTc]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 (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [^99mTc]mebrofenin from the liver to the bile (k₃). Higher doses of DTZ and CsA did not further decrease k₃ but dose-dependently decreased the uptake (k₁) and backflux (k₂) 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 [^99mTc]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.

中文翻译：

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在大鼠中使用[99mTc] mebrofenin显像对靶向抑制肝细胞中小管MRP2活性的药理学方案的验证。

多药耐药相关蛋白2（MRP2）介导药物和代谢产物的胆汁排泄。[ ^99m Tc]美洛芬宁可以用作肝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[ ^99m Tc]美洛芬宁的肝吸收取决于有机阴离子转运多肽（OATP）的活性，因此需要一种安全抑制肝MRP2的安全方案，以研究每种转运蛋白系统的内在作用。地尔硫卓（DTZ）和环孢菌素A（CsA）首先在体外被证实是有效的MRP2抑制剂。在大鼠中进行动态采集（每组n = 5–6）以评估[ ^99m抑制剂剂量增加后，Tc] mebrofenin在肝脏，肠和心脏血库中。使用多普勒超声评估其对肝血流的影响（n = 4）。DTZ（sc，10 mg / kg）和低剂量CsA（iv，0.01 mg / kg）选择性降低[ ^99m Tc]美洛芬宁从肝脏到胆汁的转移（k ₃）。高剂量的DTZ和CsA并没有进一步降低k _3，但是剂量依赖性地降低了摄取（k ₁）和反流（k ₂）血液和肝脏之间的速率常数。高剂量的DTZ（iv，3 mg / kg）而不是CsA（iv，5 mg / kg）显着降低门静脉和肝动脉的血流量。可以在体内实现对肝MRP2活性的靶向药理抑制，而不会影响OATP活性和肝血流量。有必要进行临床研究以验证[ ^99m Tc]美洛芬宁与低剂量CsA的结合作为一种新颖的底物/抑制剂对，以阐明OATP和MRP2活性在肝脏疾病中的作用。