DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 471

family among rodents and humans. Among human OATPs, only OATP4C1 is mainly
expressed in the kidneys. 61 Oatp1a3v1 (previous name: OAT-K1) 62 and Oatp1a3v2
(previous name: OAT-K2) 63 are expressed specifically in the rat. Oatp1a1 (previous
name: oatp1), 59 Oatp1a5 (previous name: oatp3), 64 Oatp1a6 (previous name: oatp5), 65
and Oatp4c1 61 are expressed in rodent kidneys. The orthologs of these isoforms,
except OATP4C1, are absent in humans. Because of the above-mentioned remarkable
species differences in OATP, it is difficult to assign distinct physiological roles to each
OATP in the kidneys. The role of OATP4C1 in the kidneys is evident. There are several
important substances that are preferable substrates for the OATP family, which are
excreted primarily via the kidneys. One example is digoxin, a cardiac glycoside. The
exit pathway for digoxin at the apical membrane of proximal tubular cells has been
assumed to be an ATP-dependent efflux pump, P-glycoprotein (Pgp). 66 However,
the basolateral entrance for digoxin was as yet unknown. Recently, OATP4C1 has
been revealed to be a digoxin transporter. 61 OATP4C1 is expressed exclusively in
the basolateral membrane of proximal tubular cells and mediates the high-affinity
transport of digoxin ( K m = 7.8 μ M) and ouabain ( K m = 0 . 38 μ M), as well as thyroid

hormones such as triiodothyronine ( K m = M). These data suggest that OATP4C1

is a digoxin transporter localized in the basolateral membrane of proximal tubular cells
and plays a central role in the renal elimination of digoxin.

5 . 9 μ

Sodium/Phosphate Transporter Type I Family SLC17 Molecular studies have de-
termined that type 1 phosphate transporters (NPT1s; SLC17), a family of proteins
initially characterized as phosphate carriers, expressed at the apical membrane of
renal proximal tubular cells, mediate the transport of organic anions (Figure 15.1). 67
Mouse and human NPT1 were shown to mediate the transport of various organic
anions in a chloride-dependent manner. Moreover, because human NPT1 exhibits
an affinity for PAH, corresponding to previous reports using brush border membrane
vesicles, NPT1 is also suggested as representing the classical voltage-dependent PAH
transporter. 13 However, an influence of the membrane potential on PAH transport
was not demonstrated. 68 We isolated a novel transport protein with the properties of
voltage-driven organic anion transport from pig kidney cortex by expression cloning
in Xenopus oocytes. 69 A cDNA encoding a 467-amino acid peptide was designated
as OATv1 (voltage-driven organic anion transporter 1). The predicted amino acid
sequence of OATv1 exhibited 60 to 65% identity to those of human, rat, rabbit, and
mouse NPT1/Npt1. OATv1 mediates the transport of PAH, estrone sulfate, estradiol-
17 -glucuronide, and urate. PAH transport via OATv1 was affected by the changes

in membrane potential. This transport protein is localized at the apical membrane
of renal proximal tubule, which is consistent with the proposed localization of a
voltage-driven organic anion transporter. OATv1 has therefore been proposed to play
an important role in the excretion of various organic anions, including PAH and urate
driven by membrane voltage through the apical membrane of the tubular epithelial
cells into the urine.

Peptide Transporter Family SLC15 Peptide transporters are involved in electrogenic,
H + -dependent transport of small peptides as well as various peptidelike drugs, 70 , 71