Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. May 22, 2022; 13(3): 73-84
Published online May 22, 2022. 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
Parker Giroux, Patrick B Kyle, Chalet Tan, Joseph D Edwards, Michael J Nowicki, Hua Liu
Parker Giroux, Joseph D Edwards, Michael J Nowicki, Hua Liu, Division of Pediatric Gastroenterology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, United States
Patrick B Kyle, Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, United States
Chalet Tan, Department of Pharmaceutics and Drug Delivery, University of Mississippi, Oxford, MS 38677, United States
Author contributions: Giroux P, Nowicki MJ, Tan C and Liu H participated in conception and research design; Giroux P, Kyle PB, and Liu H conducted experiments; Giroux P, Nowicki MJ, Tan C, Edwards JD, and Liu H performed data analysis and interpretation; Giroux P, Kyle PB, Nowicki MJ, Tan C, Edwards JD, and Liu H wrote or contributed to the reversion of the manuscript; and all authors have read and approved the final manuscript.
Institutional review board statement: The study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center.
Institutional animal care and use committee statement: The study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center.
Conflict-of-interest statement: The authors declare that there is no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hua Liu, MD, Assistant Professor, Division of Pediatric Gastroenterology, Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States. hliu@umc.edu
Received: August 9, 2021
Peer-review started: August 9, 2021
First decision: October 16, 2021
Revised: October 26, 2021
Accepted: April 21, 2022
Article in press: April 21, 2022
Published online: May 22, 2022
Processing time: 281 Days and 20.1 Hours
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: Cholestasis; Digoxin clearance; Organic anion transporting polypeptides; P-glycoproteins/multidrug resistance 1; Bile duct ligation

Core Tip: The heart, kidney and liver are inextricably linked by virtue of blood flow and metabolism of medications. Cholestasis induced by bile duct ligation resulted in liver functional injury and a decrease in digoxin clearance. Quantitative western blot and real-time polymerase chain reaction demonstrated the up or down regulation of membrane transporters multidrug resistance 1, organic anion transporting polypeptides (OATP)1A4, and OATP4C1 in the liver, kidney, and intestine. Cell digoxin transporters are regulated during cholestasis which is favorable for increasing digoxin excretion.