Regional expression levels of drug transporters and metabolizing enzymes along the pig and human intestinal tract and comparison with Caco-2 cells

Abstract

Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to better characterize available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum; N=4), in human intestine (jejunum; N=9) and Caco-2 cells. Expression of the included transporters and enzymes was in general well comparable between porcine and human intestinal tissue, though BCRP, MCT5, MDR1, MRP1, MRP3 (~2-fold) and OATP4A1 (~6-fold) was higher expressed in pig compared to human jejunum. Alternatively, expression level of relevant transporter proteins (GLUT1, OATP4A1, MRP2, MRP1 and OATP2B1) was significantly higher (3- to 130-fold) in Caco-2 cells compared to human jejunum. Moreover, all examined CYPs showed at least a five-fold lower gene expression in Caco-2 cells compared to human jejunum, with the smallest differences for CYP1A1 and CYP3A5 and the largest difference for CYP3A4 (871-fold higher expression in human jejunum compared to Caco-2 cells). In conclusion, a comprehensive overview is provided of the expression levels of clinically relevant transporter proteins and metabolic enzymes in porcine and human intestinal tissue, and Caco-2 cells, which may assist in deciding upon the most suitable model to further improve our understanding of processes that determine intestinal absorption of compounds.