Y. Emi et al., ROLE OF P-GLYCOPROTEIN AS A SECRETORY MECHANISM IN QUINIDINE ABSORPTION FROM RAT SMALL-INTESTINE, Journal of pharmaceutical sciences, 87(3), 1998, pp. 295-299
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.