DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 473

the efflux of PAH and several small hydrophilic organic anions, such as urate, cAMP,
and cGMP, into the tubular lumen. 80
Breast Cancer Resistance Protein/ABCG2 Breast cancer resistance protein (BCRP)
is the second isoform of the WHITE subfamily of the human ATP-binding cassette
(ABC) transporter superfamily and thus also named as ABCG2. 81 BCRP is called
a half-transporter because it contains a single N-terminal ATP-binding cassette fol-
lowed by six putative transmembrane segments and may function as a homodimer or
homotetramer. BCRP expression was detected in several hematological malignancies
and solid tumors, suggesting its role in clinical drug resistance of cancer. 81 BCRP can
accept a variety of organic anions, such as sulfated conjugates of steroids and xenobi-
otics in addition to the anticancer drugs mitoxantrone, topotecan, and methotrexate. 81
Bcrp mRNA levels were high in rodent kidneys 82 but BCRP seems unlikely to play
an important role in renal secretion of drugs in humans as in rodents, since there is
little expression of BCRP in human kidney.
15.2.2. Organic Cation Transporters
In this part we give an overview of molecular information concerning individual
organic cation transporters (OCT family and P-glycoprotein) and their possible roles
in renal drug elimination (Table 15.1 and Figure 15.1).
Organic Cation Transporter Family SLC22
OCT1 OCT1 was cloned from rat kidney and characterized functionally in 1994
using Xenopus oocytes. 83 Rat Oct1 (rOct1) mRNA was expressed in the liver, intestine,
and kidney. rOct1 protein was localized to the basolateral membrane of the S1 and S2
segments of renal proximal tubules. 84 , 85 When expressed in oocytes, rOct1 stimulated
its TEA uptake and inhibited by diverse organic cations. 83 Electrophysiological study
indicated that the rOct1-mediated cation transport is electrogenic. TEA uptake was
decreased by acidifying the medium pH, suggesting that rOct1-mediated uptale was
pH sensitive. The human OCT1 mRNA expression was observed predominantly in
the liver. 86 , 87 Although it has been shown that hydrophobicity is a major determinant
of drug interactions with OCT1, 88 significant differences have been found among
the cloned OCT1 transporters from different species in terms of the kinetics and
substrate selectivities. 89 These findings suggest that OCT1 may be responsible, in
part, for interspecies differences in the disposition of organic cations.
OCT2 Oct2 was isolated from a rat kidney cDNA library by Okuda et al. 90 Rat
Oct2 (rOct2) mRNA was expressed mainly in the kidney, but not in the liver,
lung, or intestine. rOct2 was localized to the basolateral membrane of the proxi-
mal tubules. 91 , 92 rOct2 has been shown to interact with various cationic compounds,
such as N -methyl-4-phenylpyridinium (MPP + ), cimetidine, NMN, nicotine, quinine,
and quinidine. 85 When expressed in oocytes, rOct2-mediated TEA uptake was sup-
pressed by the replacement of Na + with K + , thus indicating that the rOct2 transport