Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

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Abstract

Emerging information suggests that liver pathological states may affect the expression and function of membrane transporters in the gastrointestinal tract and the kidney. Altered status of the transporters could affect drug as well as endogenous compounds handling with subsequent clinical consequences. It seems that changes in intestinal and kidney transporter functions provide the compensatory activity of eliminating endogenous compounds (e.g., bile acids) generated and accumulated due to liver dysfunction. A literature search was conducted on the Ovid and PubMed databases to select relevant in vitro, animal and human studies that have reported expression, protein abundance and function of the gastrointestinal and kidney operating ABC (ATP-binding cassette) transporters and SLC (solute carriers) carriers. The accumulated data suggest that liver failure-associated transporter alterations in the gastrointestinal tract and kidney may affect drug pharmacokinetics. The altered status of drug transporters in those organs in liver dysfunction conditions may provide compensatory activity in handling endogenous compounds, affecting local drug actions as well as drug pharmacokinetics.

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Most cited references 72

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Membrane transporters in drug development.

Kathleen M. Giacomini, Shiew-Mei Huang, Donald Tweedie … (2010)

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

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Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.

Udayan Apte, Tiangang Li (2015)

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug, and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport, and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis.

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Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.

Jeffrey B. Jones, Steve Kliewer, Robert Edwards … (2002)

The multidrug resistance-associated protein 2 (MRP2, ABCC2), mediates the efflux of several conjugated compounds across the apical membrane of the hepatocyte into the bile canaliculi. We identified MRP2 in a screen designed to isolate genes that are regulated by the farnesoid X-activated receptor (FXR, NR1H4). MRP2 mRNA levels were induced following treatment of human or rat hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands. In addition, we have shown that MRP2 expression is regulated by the pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3). Thus, treatment of rodent hepatocytes with PXR or CAR agonists results in a robust induction of MRP2 mRNA levels. The dexamethasone- and pregnenolone 16alpha-carbonitrile-dependent induction of MRP2 expression was not evident in hepatocytes derived from PXR null mice. In contrast, induction of MRP2 by phenobarbital, an activator of CAR, was comparable in wild-type and PXR null mice. An unusual 26-bp sequence was identified 440 bp upstream of the MRP2 transcription initiation site that contains an everted repeat of the AGTTCA hexad separated by 8 nucleotides (ER-8). PXR, CAR, and FXR bound with high affinity to this element as heterodimers with the retinoid X receptor alpha (RXRalpha, NR2B1). Luciferase reporter gene constructs containing 1 kb of the rat MRP2 promoter were prepared and transiently transfected into HepG2 cells. Luciferase activity was induced in a PXR-, CAR-, or FXR-dependent manner. Furthermore, the isolated ER-8 element was capable of conferring PXR, CAR, and FXR responsiveness on a heterologous thymidine kinase promoter. Mutation of the ER-8 element abolished the nuclear receptor response. These studies demonstrate that MRP2 is regulated by three distinct nuclear receptor signaling pathways that converge on a common response element in the 5'-flanking region of this gene.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 10 August 2020

Publication date Collection: August 2020

Volume: 21

Issue: 16

Electronic Location Identifier: 5737

Affiliations

[1 ]Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland

[2 ]Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18051 Rostock, Germany; stefan.oswald@ 123456med.uni-rostock.de

[3 ]Department of Integrated Dentistry, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland; agdro@ 123456pum.edu.pl

Author notes

[* ]Correspondence: drozdzik@ 123456pum.edu.pl ; Tel.: +48-91-4661589; Fax: +48-91-466-1600

Author information

Marek Droździk https://orcid.org/0000-0002-6191-7168

Agnieszka Droździk https://orcid.org/0000-0002-1119-3317

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Publisher ID: ijms-21-05737

DOI: 10.3390/ijms21165737

PMC ID: 7461118

PubMed ID: 32785140

SO-VID: 85ff0506-c658-4ef9-9705-eb1dd660dcf2

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Extrahepatic Drug Transporters in Liver Failure: Focus on Kidney and Gastrointestinal Tract

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Abstract

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Drug_transporters

Most cited references 72

Membrane transporters in drug development.

Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.

Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.

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