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
ARTICLE HIGHLIGHTS
Research background

The heart and liver are inextricably linked by virtue of blood flow and metabolism of medications. Drugs with biliary elimination, such as digoxin, decrease clearance with cholestasis.

Research motivation

We performed this study to better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.

Research objectives

The efflux transporter, multidrug resistance 1 (MDR1), and influx transporters, organic anion transporting polypeptides (OATP)1A4 and OATP4C1 in kidney, intestine and liver were examined.

Research methods

Twelve adult Sprague Dawley 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 MDR1, OATP1A4 and OATP4C1 by quantitative western blot and real-time polymerase chain reaction.

Research results

Digoxin clearance was decreased and liver function, but not renal function, was impaired in BDL rats. BDL resulted in significant up-regulation of MDR1 expression in the liver and kidney and its down-regulation in the small intestine. OATP1A4 was up-regulated in the liver but down-regulated in intestine after BDL. OATP4C1 expression was markedly increased in the kidney following BDL.

Research conclusions

The results suggest that cell membrane transporters of digoxin are regulated during cholestasis. These regulations are favorable for increasing digoxin excretion in kidney and decreasing its absorption from intestine in order to compensate the reduced digoxin clearance due to cholestasis.

Research perspectives

The current study was designed as an exploratory research for providing clues for future study in this field. Previous studies on the transporters in kidney and intestine were done only by in vitro experiments. To the best of our knowledge, the current report is the first study to investigate the regulation of the digoxin transporters in kidney and intestine in animal model of cholestasis. Our results does demonstrate that the cell membrane transporters were regulated which is in favor of digoxin excretion during cholestasis. To confirm our finding, more detailed PK studies need to be done, for example, tissue distributions of digoxin and digoxin concentrations in urine and in intestine. Knock-out (KO) animal lacking the transporters, especially tissue-specific KO, will be a powerful tool in further study.