Evaluating the regulation of transporter proteins and P-glycoprotein in rats with cholestasis and its implication for digoxin clearance

Parker Giroux; Patrick B Kyle; Chalet Tan; Joseph D Edwards; Michael J Nowicki; Hua Liu

doi:10.4291/wjgp.v13.i3.73

Evaluating the regulation of transporter proteins and P-glycoprotein in rats with cholestasis and its implication for digoxin clearance

World J Gastrointest Pathophysiol. 2022 May 22;13(3):73-84. doi: 10.4291/wjgp.v13.i3.73.

Authors

Parker Giroux¹, Patrick B Kyle², Chalet Tan³, Joseph D Edwards¹, Michael J Nowicki¹, Hua Liu⁴

Affiliations

¹ Division of Pediatric Gastroenterology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, United States.
² Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, United States.
³ Department of Pharmaceutics and Drug Delivery, University of Mississippi, Oxford, MS 38677, United States.
⁴ Division of Pediatric Gastroenterology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, United States. hliu@umc.edu.

Abstract

Background: 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.

Aim: To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.

Methods: 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 t-test, while independent t-test was employed to compare the means between sham and BDL groups.

Results: 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.

Conclusion: 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.

Keywords: Bile duct ligation; Cholestasis; Digoxin clearance; Organic anion transporting polypeptides; P-glycoproteins/multidrug resistance 1.