DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 506

Pgp may transport a number of therapeutic agents and possibly lead to low oral
absorption of some drugs. 41
The important role of Pgp in intestinal absorption of orally administered drugs
is also supported by a large body of in vivo evidence using Pgp knockout mice.
In contrast to humans, who have only one gene (MDR1) encoding Pgp, mice have
two genes (i.e., mdr1a and mdr1b) working together to fulfill the equivalent function
of human Pgp. Further studies demonstrated that the relative abundance of mdr1a
and mdr1b transcripts is tissue or organ specific, with mdr1a highly expressed in
intestinal epithelial cells and at the blood-brain and blood-testis barriers, whereas
mdr1b is highly expressed in the adrenal gland, pregnant uterus, and ovaries. Both
mdr1a and mdr1b genes are expressed substantially in many other tissues, including
the liver, kidney, lung, heart, and spleen. 42 , 43 Pgp knockout mice are now available
as mdr1a(-/-), mdr1b(-/-), and mdr1a/1b(-/-) (double knockouts). 43 , 44 A study by
Sparreboom et al. 45 assessed the effect of gut Pgp on the pharmacokinetics of pacli-
taxel using mdr1a(-/-) mice. The results showed that the AUC of paclitaxel was two-
and sixfold higher in mdr1a(-/-) mice than in wild-type mice after intravenous and
oral drug administration, respectively. Additionally, cumulative (0 to 96 hour) fecal
drug excretion decreased from 87% (after oral administration) and 40% (after intra-
venous administration) of the administered dose in wild-type mice to less than 3% in
mdr1a(-/-) mice. Since the biliary secretion of paclitaxel is similar between wild-type
and mdr1a(-/-) mice, the reduced fecal excretion in mdr1a(-/-) mice was attributed
to the lower intestinal Pgp-mediated secretion as compared to that of wild-type mice.
Collectively, their results suggest that intestinal Pgp not only limit the oral absorption
of paclitaxel but also mediate direct secretion of the drug from the systemic circu-
lation into the intestinal lumen. The role of Pgp in intestinal drug secretion has also
been demonstrated for digoxin, which is metabolized to a minor extent in humans.
In bile duct-ligated mice (i.e., no biliary flux into the intestinal lumen), the intestinal
secretion of digoxin was reduced from 16% of the administered dose in wild-type
mice to 1.5% in mdr1a/1b(-/-) mice. 44 Using a recently developed perfusion catheter,
which isolates human jejunal segments by inflating balloons at the desired point in-
side the lumen, Drescher et al. 46 measured the intestinal secretion of digoxin after
intravenous administration. Within 3 hours of injection, 0.45% of the dosed digoxin
(1 mg) was eliminated into a 20-cm-long segment of jejunum. Additionally, perfusion
of the isolated segment with Pgp inhibitor (quinidine) reduced intestinal secretion of
digoxin to 0.23%. When their findings were scaled up from one segment to the entire
intestine, it was estimated that at least 11% of the intravenously administered digoxin
was directly secreted into the intestinal lumen within 3 hours, and approximately half
was mediated by Pgp.
The unequivocal involvement of Pgp in intestinal drug efflux was also assessed
using excised intestinal segments mounted onto Ussing diffusion chambers. For ex-
ample, studies on the vectorial transport of digoxin across the intestinal wall demon-
strated that the efflux ratio was as high as 10-fold greater; however, this prominent
directional difference of digoxin transport diminished in mdr1a(-/-) mice. Makhey
et al. 13 investigated the mechanisms and kinetics of intestinal secretory transport
process of the anticancer drug etoposide (a topoisomerase II inhibitor) in rat or hu-
man intestine. The results showed that etoposide secretion is regionally dependent