Xiong H, Turner K C, Ward E S, Jansen P L, Brouwer K L
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
J Pharmacol Exp Ther. 2000 Nov;295(2):512-8.
Previous studies have demonstrated that phenobarbital treatment impairs the biliary excretion of acetaminophen glucuronide (AG), although the transport system(s) responsible for AG excretion into bile has not been identified. Initial studies in rat canalicular liver plasma membrane vesicles indicated that AG uptake was stimulated modestly by ATP, but not by membrane potential, HCO(3)(-), or pH gradients. To examine the role of the ATP-dependent canalicular transporter multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter (cMOAT) in the biliary excretion of AG, the hepatobiliary disposition of acetaminophen, AG, and acetaminophen sulfate (AS) was examined in isolated perfused livers from control and TR(-) (Mrp2-deficient) Wistar rats. Mean bile flow in TR(-) livers was approximately 0.3 microl/min/g of liver ( approximately 4-fold lower than control). AG biliary excretion was decreased (>300-fold) to negligible levels in TR(-) rat livers, indicating that AG is an Mrp2 substrate. Similarly, AS biliary excretion in TR(-) livers was decreased ( approximately 5-fold); however, concentrations were still measurable, suggesting that multiple mechanisms, including Mrp2-mediated active transport, may be involved in AS biliary excretion. AG and AS perfusate concentrations were significantly higher in livers from TR(-) compared with control rats. Pharmacokinetic modeling of the data revealed that the rate constant for basolateral egress of AG increased significantly from 0.028 to 0.206 min(-1), consistent with up-regulation of a basolateral organic anion transporter in Mrp2-deficient rat livers. In conclusion, these data indicate that AG biliary excretion is mediated by Mrp2, and clearly demonstrate that substrate disposition may be influenced by alterations in complementary transport systems in transport-deficient animals.
以往的研究表明，苯巴比妥治疗会损害对乙酰氨基酚葡萄糖醛酸苷（AG）的胆汁排泄，尽管负责将AG排泄到胆汁中的转运系统尚未明确。对大鼠胆小管肝细胞膜囊泡的初步研究表明，ATP对AG摄取有适度刺激作用，但膜电位、HCO₃⁻或pH梯度则无此作用。为了研究ATP依赖性胆小管转运体多药耐药相关蛋白2（Mrp2）/胆小管多特异性有机阴离子转运体（cMOAT）在AG胆汁排泄中的作用，在来自对照和TR⁻（Mrp2缺陷）Wistar大鼠的离体灌注肝脏中研究了对乙酰氨基酚、AG和对乙酰氨基酚硫酸盐（AS）的肝胆处置情况。TR⁻肝脏中的平均胆汁流量约为0.3微升/分钟/克肝脏（比对照低约4倍）。TR⁻大鼠肝脏中AG的胆汁排泄减少（>300倍）至可忽略不计的水平，表明AG是Mrp2的底物。同样，TR⁻肝脏中AS的胆汁排泄也减少（约5倍）；然而，其浓度仍可测量，这表明包括Mrp2介导的主动转运在内的多种机制可能参与AS的胆汁排泄。与对照大鼠相比，TR⁻大鼠肝脏中的AG和AS灌注液浓度显著更高。对数据的药代动力学建模显示，AG基底外侧流出的速率常数从0.028显著增加至0.206分钟⁻¹，这与Mrp2缺陷大鼠肝脏中基底外侧有机阴离子转运体的上调一致。总之，这些数据表明AG的胆汁排泄由Mrp2介导，并清楚地证明在转运缺陷动物中，底物处置可能会受到互补转运系统改变的影响。
