Abstract

Efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the intestinal wall restrict intestinal drug transport. To overcome this limitation for enteral drug absorption, galenical targeting approaches have been proposed for site-specific luminal drug release in segments of the gut, where expression of the respective absorption-limiting transporter is minimal. Therefore, expression of multidrug resistance gene 1 (MDR1) and MRP1-5 was systematically investigated in 10 healthy subjects. Biopsies were taken from different segments of the gastrointestinal tract (from duodenum and terminal ileum, as well as ascending, transverse, descending, and sigmoid colon). Gene expression was investigated by quantitative real-time PCR (TaqMan). MRP3 appeared to be the most abundantly expressed transporter in investigated parts of the human intestine, except for the terminal ileum, where MDR1 showed the highest expression. The ranking of transporter gene expression in the duodenum was MRP3 ≫ MDR1 > MRP2 > MRP5 > MRP4 > MRP1. In the terminal ileum, the ranking order was as follows: MDR1 > MRP3 ≫ MRP1 ≈ MRP5 ≈ MRP4 > MRP2. In all segments of the colon (ascending, transverse, descending, and sigmoid colon), the transporter gene expression showed the following order: MRP3 ≫ MDR1 > MRP4 ≈ MRP5 > MRP1 ≫ MRP2. We have shown, for the first time, systematic site-specific expression of MDR1 and MRP mRNA along the gastrointestinal tract in humans. All transporters showed alterations in their expression levels from the duodenum to sigmoid colon. The most pronounced changes were observed for MRP2, with high levels in the small intestine and hardly any expression in colonic segments. This knowledge may be useful to develop new targeting strategies for enteral drug delivery.