Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs, nutrients, and xenobiotics (1-3). The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ATP binding cassette (ABC) and the solute carrier (SLC) families mediate the uptake and efflux of endogenous compounds, xenobiotics, and their metabolites in hepatocytes. The activity of these transporters is an important aspect of the pharmacokinetics and dynamics of drugs and is important for drug-drug and drug-nutrient interactions. Additionally, monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis. Functional impairment or inhibition of these transport systems may lead to liver injury. Several nuclear receptors, such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), coordinately regulate the levels of important enzymes like cytochrome P450 3A4 (CYP3A4) as well as drug transporters including ABCB1 (MDR-1). Understanding of the molecular mechanisms that affect enzyme and transporter activity may contribute to the predictability of drug-drug interactions and eventually help to develop safer therapeutic regimens.
Date of publication: 2019
Author: Jack Vanden Heuvel, PhD; INDIGO Biosciences, Inc.