DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 465

organic cations: type 1 transports small hydrophilic organic cations, and type 2 trans-
ports large hydrophobic organic cations. 8 , 9
During the last decade, molecular cloning has identified several families of mul-
tispecific organic anion and cation transporters, such as organic anion transporter
(OAT), organic cation transporter (OCT), organic anion-transporting polypeptide
(OATP), sodium-phosphate transporter (NPT), peptide transporter (PEPT), nucleo-
side transporter (CNT), and the multidrug and toxin extrusion 1 (MATE1). Addi-
tional findings have also suggested ATP-dependent organic ion transporters such as
MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP) and the
breast cancer resistance protein (BCRP) to act as an efflux pump.
In this chapter we outline the present knowledge of drug transport in the kidney. The
first section is an overview of the molecular information on renal drug transporters. It
includes the key transporters associated with renal organic anions and cations, pep-
tides, and nucleosides. In the second section we focus on recent advances, particularly
the regulatory mechanisms of renal drug transporters, such as gender differences, in-
tracellular signaling, and scaffold proteins. Finally, we discuss the pharmacological
and toxicological aspects of renal drug transporters. A number of articles 10 , 11 and
reviews 12-20 concerning organic anion and cation transporters have been published.

15.2. MOLECULAR IDENTIFICATION OF RENAL
DRUG TRANSPORTERS

15.2.1. Organic Anion Transporters

Molecular cloning has identified most of the organic anion transporters to belong to
the OAT, OATP, NPT, PEPT, CNT, and MRP transporter families and BCRP (Table
15.1 and Figure 15.1). In this part we give an overview of molecular information
concerning individual organic anion transporters and their possible roles in renal
drug elimination.

Organic Anion Transporter Family SLC22

OAT1 Several research groups have cloned the first member of the OAT family
OAT1. 21-23 OAT1 is identical to the previously isolated clone, the novel kidney-
specific transporter (NKT). 24 OAT1 mRNA is expressed predominantly in the kid-
neys and weakly in the brain. In the kidneys, OAT1 protein is localized at the baso-
lateral membrane of proximal tubular cells. The OAT1-mediated uptake of PAH is
stimulated by an outwardly directed concentration gradient of dicarboxylates such
as -ketoglutarate, which is consistent with the previous notion that OAT1 is an or-

ganic anion-dicarboxylate exchanger. 25 The substrate selectivity of OAT1 is markedly
broad, and these substrates include endogenous substances, such as dicarboxylates,
cyclic nucleotides, and prostaglandins, and exogenous substances, such as various
anionic drugs and environmental compounds. 26 The affinities of OAT1 for these
compounds are similar to values reported for the basolateral PAH transporter, 3 and