Abstract
Robust, predictive ex vivo/in vitro models to study intestinal drug absorption by passive and active transport mechanisms are scarce. Membrane transporters can significantly impact drug uptake and transporter-mediated drug–drug interactions can play a pivotal role in determining the drug safety profile. Here, the presence and activity of seven clinically relevant apical/basolateral drug transporters found in human jejunum were tested using ex vivo porcine intestine in a Ussing chamber system. Experiments using known substrates of peptide transporter 1 (PEPT1), organic anion transporting polypeptide (OATP2B1), organic cation transporter 1 (OCT1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi drug resistance-associated protein 2 and 3 (MRP2 and MRP3), in the absence and presence of potent inhibitors, showed that there was a statistically significant change in apparent intestinal permeability Papp,pig (cm/s) in the presence of the corresponding inhibitor. For MRP2, a transporter reportedly present at relatively low concentration, although Papp,pig did not significantly change in the presence of the inhibitor, substrate deposition (QDEP) in the intestinal tissue was significantly increased. The activity of the seven transport proteins was successfully demonstrated and the results provided insight into their apical/basolateral localization. In conclusion, the results suggest that studies using the porcine intestine/Ussing chamber system, which could easily be integrated into the drug development process, might enable the early-stage identification of new molecular entities that are substrates of membrane transporters.
Highlights
The human intestinal wall is a highly complex anatomical barrier with several challenging physiological functions
Many orally administered drugs are absorbed by passive transport; some are substrates of membrane transporters that facilitate uptake across the intestinal wall and entry into the hepatic portal vein, whereas others are eliminated by efflux transporters localized in the enterocytes [3]
We recently demonstrated that apparent permeability coefficients Papp,pig measured using ex vivo porcine intestine in an Ussing chamber set-up showed a good correlation to effective permeability coefficients Peff,human reported in humans in vivo [45]
Summary
The human intestinal wall is a highly complex anatomical barrier with several challenging physiological functions. It must regulate the absorption of a wide variety of chemical entities with different physicochemical properties, which are vital for our well-being, but at the same time, prevent the entry of potentially harmful or toxic substances. Many orally administered drugs are absorbed by passive transport; some are substrates of membrane transporters that facilitate uptake across the intestinal wall and entry into the hepatic portal vein, whereas others are eliminated by efflux transporters localized in the enterocytes [3]. Biomedicines 2020, 8, 340; doi:10.3390/biomedicines8090340 www.mdpi.com/journal/biomedicines (DDI)—concurrent presence of transporter substrates and/or inhibitors can have a major effect on drug uptake and result in a highly variable oral bioavailability [4]. Identification of drug candidates that are transporter substrates at an early stage of drug development is crucial
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