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

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.

In Vivo Gene Expression Profile of Human Intestinal Epithelial Cells: From the Viewpoint of Drug Metabolism and Pharmacokinetics

“…Several uptake transporters, including organic anion transporting polypeptide (OATP) family members, peptide transporter 1 (PEPT1; SLC15A1), and ileal apical sodium/bile acid co-transporter (ASBT; SLC10A2) are highly expressed at the apical membrane of small intestinal epithelial cells (Giacomini et al, 2010;Droździk et al, 2020). In addition, several efflux pumps, including breast cancer resistance protein (BCRP; ABCG2) and P-glycoprotein (P-gp; MDR1, ABCB1), are highly expressed at the apical membrane of small intestinal epithelial cells (Giacomini et al, 2010;Droździk et al, 2020). On the other hand, heteromeric organic solute transporter (OSTα-OSTβ) and multidrug resistance protein 3 (MRP3; ABCC3) are highly expressed at the basolateral membrane of small intestinal epithelial cells (Giacomini et This article has not been copyedited and formatted.…”

Does renal function matter for polymyxin B?

“…It can be hypothesized that interactions at the level of the kidney and liver may alter polymyxin B clearance. Liver failure results in a host of changes for drug transporters, none of which have been explored to our knowledge for polymyxin B 8 . Polymyxin B uptake into renal cells is primarily through the apical membrane via the urine 9,10 .…”

“…Liver failure results in a host of changes for drug transporters, none of which have been explored to our knowledge for polymyxin B. 8 Polymyxin B uptake into renal cells is primarily through the apical membrane via the urine. 9,10 Damage to reuptake transporters such as PEPT1/2 and OCTN1/2 could cause increased clearance of polymyxin B, potentially offsetting any decreases in clearance from other mechanisms when acute kidney injury occurs.…”

Renal Transporter Alterations in Patients with Chronic Liver Diseases: Nonalcoholic Steatohepatitis, Alcohol-Associated, Viral Hepatitis, and Alcohol-Viral Combination

“…This is implicit in the Food and Drug Administration (FDA) requirement to evaluate select transporters in drug-drug interaction studies (FDA, 2022). Since the liver and kidney are considered the primary organs involved in ADME processes, knowing their respective transporter expression and function during disease states is imperative for preventing ADRs (Droździk et al, 2020). Specifically, hepatic transporter alterations in chronic liver diseases (CLD) have been well characterized and are considered when predicting ADRs through shifts in pharmacokinetic profiles (More et al, 2013;Wang et al, 2016;Vildhede et al, 2020).…”