Role of basolateral efflux transporters in intestinal absorption of drugs and prodrugs

Polarized expression and cooperation of drug transporters in epithelial cells are critical in governing systemic exposure and thereafter drug actions. However, mechanisms for the basolateral efflux of hydrophilic compounds from intestine remain elusive. Studies described in this dissertation provide novel insights about the role of basolateral transporters in intestinal drug absorption: they are critical for the transcellular transport of hydrophilic drugs when apical transporters mediate uptake efficiently, or when prodrugs are metabolized into hydrophilic drugs intracellularly after diffusion through the apical membrane. Investigation of the absorptive transport of fexofenadine in Caco-2 cells provided evidence for a vectorial transport system in its intestinal absorption, consisting of organic anion transporting polypeptide 2B1 for apical uptake and multidrug-resistance associated protein 3 (MRP3) for basolateral egress. The MRP inhibitor decreased the absorptive transport of fexofenadine moderately; further, this decrease was more pronounced when Pglycoprotein was also inhibited. It appears that apical efflux by P-glycoprotein may be the rate-limiting step in intestinal absorption of fexofenadine; however, MRP3-mediated basolateral efflux may control its absorption where P-glycoprotein expression/effect is low. Adefovir dipivoxil, an ester prodrug of adefovir with improved bioavailability, diffuses across cell membranes readily and is rapidly hydrolyzed to adefovir intracellularly. In MRP4-knockdown Caco-2 cells, basolateral availability of adefovir upon dosing the apical compartment with [3H]adefovir dipivoxil was reduced at the level comparable to the chemical inhibition of MRPs in wild-type cells. Results showed that MRP4 is localized in the basolateral membrane of Caco-2 cells and mediates the basolateral efflux of adefovir generated intracellularly. The diamidine drug, furamidine, was identified as a substrate for organic cation transporter 1 (OCT1), an intestinal basolateral transporter. It mediates efflux of furamidine at much lower rate than its uptake. A diamidoxime prodrug of furamidine diffuses into OCT1 transfected MDCKII cells, and is metabolized intracellularly to furamidine, which egresses across the basolateral membrane by OCT1-mediated transport. However, its significance is still questionable under physiological conditions due to the inefficient efflux and the low expression in vivo. Overall, this work has provided new insights about carrier-mediated basolateral efflux mechanisms and defined when and how these basolateral transporters affect intestinal drug absorption