ROLE OF P-GLYCOPROTEIN AS A SECRETORY MECHANISM IN QUINIDINE ABSORPTION FROM RAT SMALL-INTESTINE

The intestinal transport of quinidine was characterized in rat small i ntestine, using the Ussing-type chamber under short-circuited conditio ns. In the short-circuited condition, quinidine transport was predomin antly secretory and the transport rate in jejunum was 3.5 times larger in the secretory direction than that in the absorptive direction. The secretion of quinidine was found to be dependent upon its concentrati on and to be via a carrier-mediated system in both jejunum and ileum. Although the kinetic characteristic of the carrier-mediated secretion of quinidine was very similar in jejunum and ileum, its contribution w as much greater in jejunum because of a higher passive diffusion compo nent in ileum. The secretion of quinidine, well-known as an inhibitor of P-glycoprotein, was inhibited significantly and its absorption was enhanced significantly by several substrates of P-glycoprotein includi ng verapamil, diltiazem, and digitoxin in jejunum. These phenomena wer e also observed by the addition of 2,4-dinitrophenol. Furthermore, the voltage-clamp studies indicated that the inhibition of quinidine secr etion occurred in the transcellular pathway. On the other hand, neithe r tetraethylammonium nor p-aminohippuric acid affected the transport o f quinidine. Quinidine was also recognized to inhibit the secretion an d to promote the absorption of substrates of P-glycoprotein, chlorprom azine, and verapamil. These results strongly suggest that quinidine is not only an inhibitor but also a substrate of P-glycoprotein and that the P-glycoprotein-mediated secretory flux acts as a barrier to quini dine absorption in the small intestine, especially jejunum.