Giroux Parker, Kyle Patrick B, Tan Chalet, Edwards Joseph D, Nowicki Michael J, Liu Hua
Division of Pediatric Gastroenterology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, United States.
Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, United States.
World J Gastrointest Pathophysiol. 2022 May 22;13(3):73-84. doi: 10.4291/wjgp.v13.i3.73.
Cardiac and hepatic functionality are intertwined in a multifaceted relationship. Pathologic processes involving one may affect the other through a variety of mechanisms, including hemodynamic and membrane transport effects.
To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.
Twelve adult rats were included in this study; baseline hepatic and renal laboratory values and digoxin pharmacokinetic (PK) studies were established before evenly dividing them into two groups to undergo bile duct ligation (BDL) or a sham procedure. After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction. Data were analyzed using SigmaStat 3.5. Means between pre-surgery and post-surgery in the same experimental group were compared by paired -test, while independent test was employed to compare the means between sham and BDL groups.
Digoxin clearance was decreased and liver function, but not renal function, was impaired in BDL rats. BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine. Organic anion transporting polypeptides (OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL. OATP4C1 expression was markedly increased in the kidney following BDL.
The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis. These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.
心脏和肝脏功能通过多方面的关系相互交织。涉及其中一个器官的病理过程可能通过多种机制影响另一个器官，包括血流动力学和膜转运效应。
为了更好地理解肝外胆汁淤积对涉及地高辛的膜转运体调节的影响及其对地高辛清除率的意义。
本研究纳入12只成年大鼠；在将它们平均分为两组进行胆管结扎（BDL）或假手术之前，先测定基线肝脏和肾脏实验室值以及地高辛药代动力学（PK）研究。7天后完成重复的地高辛PK研究，并采集组织样本，通过定量蛋白质免疫印迹法和实时聚合酶链反应测定细胞膜转运蛋白的表达。使用SigmaStat 3.5分析数据。同一实验组手术前和手术后的均值采用配对t检验进行比较，而独立样本t检验用于比较假手术组和BDL组的均值。
BDL大鼠的地高辛清除率降低，肝功能受损，但肾功能未受损。BDL导致肝脏和肾脏中多药耐药蛋白1表达显著上调，而在小肠中则下调。BDL后肝脏中有机阴离子转运多肽（OATP）1A4上调，但在肠道中下调。BDL后肾脏中OATP4C1表达明显增加。
结果表明，肝外胆汁淤积期间地高辛的细胞膜转运体受到调节。这些调节有利于增加地高辛在肾脏中的排泄并减少其在肠道中的吸收，以补偿胆汁淤积导致的地高辛清除率降低。
