DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 472

such as -lactam antibiotics, angiotensin-converting enzyme (ACE) inhibitors, and

anticancer drugs. Two peptide transporters, designated as PEPT1 and PEPT2, have
been cloned. 70 , 71 PEPT1, a low-affinity/high-capacity transporter, was first cloned
from the rabbit intestine and subsequently from rat and human. Rat Pept1 was localized
to the apical side of intestinal epithelial cells 72 and in early regions (S1 segments) of
apical proximal tubules. 73 PEPT2, a high-affinity/low-capacity transporter, appeared
to have different tissue localization than PEPT1, in that PEP2 is highly expressed
in the kidney but not in the intestine. Rat Pept2 was localized to the apical side of
the proximal tubule in more distal regions (S3 segments). 73 Generally, substrates for
Pept2 are similar to those of Pept1, although their affinities are different.

Nucleoside Transporter Family SLC28 Nucleoside transporters in the the concen-
trative inwardly directed Na + /nucleoside cotransport system (CNT family; SLC28) 74
and the equilibrative bidirectional facilitators (ENT family; SLC29) 75 play critical
roles in nucleoside salvage pathways, where they mediate the first step of nucleotide
biosynthesis. In addition, these transporters work in concert to terminate adenosine
signaling. CNT family members are crucial determinants of response to a variety
of anticancer and antiviral nucleoside analogs, as they modulate the entry of these
analogs into target tissues. Furthermore, this family is involved in the absorption and
disposition of many nucleoside analogs.

Multidrug Resistance-Associated Protein Family ABCC The MRP family consists
of primarily active transporter with ATP-binding cassette motifs. The prototype of this
family is Pgp, 66 which extrudes various hydrophobic molecules, particularly antineo-
plastic compounds, such as vincristine, vinblastine, adriamycin, and daunorubicin,
and it confers multidrug resistance on cancer cells. 76 MRP1 and MRP2 were isolated
from cancer cells with multidrug resistance that do not express Pgp. In addition to
antineoplastic drugs, MRP2 transports glucronides and cysteine conjugates, and it is
expressed in the canalicular membrane of hepatocytes. 13 MRP2-deficient mice lack
the activity to extrude conjugate anions from the liver, thus resulting in the phenotype
of the Dubin-Johnson syndrome. 77 To date, many isoforms have been identified in
the MRP family, 13 , 78 and several of these isoforms are expressed in the apical mem-
brane of proximal tubular cells (Figure 15.1). MRP members in proximal tubular
cells supposedly function as an extrusion pump for organic anions from the apical
membrane, especially large and hydrophobic organic anions. Regarding the renal
physiology and pharmacology, particular attention should be paid to two isoforms:
MRP2 and MRP4. MRP2 has been shown to transport PAH, but its affinity for PAH
is low ( K m =

2 mM). The observation that the renal excretion of PAH in isolated
perfused kidneys from Mrp2-deficient rats is not significantly different from those
in the kidneys from wild-type rats suggests a modest contribution of MRP2, if any,
to the efflux of PAH. 79 In contrast, human MRP4, which is also localized in the api-
cal membrane of proximal tubular cells, transports PAH with a much higher affinity
( K m = M) compared with MRP2. Furthermore, real-time PCR and Western blot

analysis showed that the renal cortical expression of MRP4 is approximately fivefold
higher than that of MRP2. 79 These data demonstrate that MRP4 plays a certain role in

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