DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 502

gene expression in the duodenum was MRP3 MDR1 > MRP2 > MRP1. In the

terminal ileum the ranking order was MDR1 MRP2. In all

segments of the colon (ascending, transverse, descending, and sigmoid colon) trans-
porter gene expression increased in the order MRP3

> MRP3 MRP1 >

MRP2.
A similar study revealed that the jejunal ABC transporter expression levels have the
following rank: BCRP =

MDR1 > MRP1

MDR1 = MRP3 = MRP1. 15

ABC transporters are often restricted to the specific cellular domains on particular
cell types in the gastrointestinal tract. For example, it has been shown that MRP1
is present mainly at the basolateral membrane of crypt cells (e.g., Paneth cells) in
the small intestine; however, its expression in the differentiated enterocytes at the tip
of villi cannot be detected. 16 P-gp expression along the crypt-villus axis was also
unevenly distributed in rat ileum, with the highest level in villus cells, but it is barely
detectable in crypt epithelium. 17 Similarly, the subcellular localization of MRP2 in
polarized intestinal epithelial cells was investigated using high-resolution microscopy
techniques after immunostaining. The results unequivocally demonstrated apical ex-
pression in superficial columnar epithelial cells. 18
Another transport family that is involved in drug absorption and disposition is the
solute carrier (SLC) family. The members within the SLC superfamily are responsible
for the transport of a variety of endogenous and exogenous substances, such as amino
acids, glucose, oligopeptides, antibiotics, nonsteroid anti-inflammatory agents, and
antitumor and anti-HIV drugs. Data currently available indicate that drug transport-
relevant SLC members in intestine include (1) solute carrier organic anion transporter
families (SLCO subfamilies) such as SLCO1A2 (OATP-A) and SLCO2B1 (OATP-
B); and (2) solute carrier family 15 (SLC15A subfamily), such as SLC15A1 (PepT1).
SLC22A members such as organic anion or cation transporters (OATs or OCTs)
have also been identified in the intestine, but they seem to be of greater importance
for transporting small endogenous molecules in kidney. In this chapter, only well-
characterized and drug transport-relevant SLC members are described.

MRP 2 >

16.4. IMPACT OF SMALL INTESTINAL TRANSPORTERS ON ORAL
ABSORPTION OF DRUGS

As discussed in Section 16.3, intestinal drug absorption is the sum of transport via
several different pathways. Since paracellular transport and transcytosis do not play
a significant role in the intestinal absorption of most modern new chemical entities, 19
these two components can be ignored in equation (8). In this case, the rate of drug
absorption is controlled only by passive diffusion and carrier-mediated transport. If
carrier-mediated transport ( J c ) is replaced by the Michaelis-Menton equation, and
passive transcellular diffusion ( J m ) with the product of passive permeability ( P m ) and
drug concentration in intestinal lumen ( C ), apparent intestinal drug transport can be
depicted as

J max C
K m +

J e = J c + J m =

C +

P m C (9)