ORGANIC CATION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 12

2.1. INTRODUCTION
Renal elimination, including both passive glomerular filtration and active tubular
secretion, is a major route of clearance for many drugs and drug metabolites. Active
secretion of drugs by the kidney takes place primarily in the renal proximal tubule,
where drug transporters facilitate the flux of drug molecules from the blood to the
tubular lumen for excretion. As early as 1947, it was recognized that transport systems
exist that aid in the elimination of a variety of structurally diverse organic cations,
including drugs and toxic xenobiotics, as well as their metabolites. 1 Prior to the
molecular cloning of organic cation transporters, it had been shown that uptake of low-
molecular-weight organic cations into the renal proximal tubule (the first step in active
secretion of organic cations) is facilitated by a polyspecific membrane potential-
sensitive transport system. Efflux of organic cations into the tubular lumen, the second
step in active tubular secretion, was shown to occur via an H + - or cation-exchange
mechanism. Additionally, uptake of organic cations into other tissues, such as hepatic
uptake, or transport across the blood-brain barrier, was known to display properties
of protein-mediated transport across the plasma membrane (e.g., saturability, and
sensitivity to temperature, membrane potential, and small-molecule inhibitors).
The first member of the organic cation transporter (OCT) family [rat OCT1
(rOCT1)] was identified in rat by expression cloning from rat kidney. 2 This was fol-
lowed quickly by homology cloning of other OCT isoforms in rodents and human. 3 − 13
Of the membrane transporters cloned to date, three have been identified as members
of the basolateral (membrane potential-driven) organic cation transporter system:
OCT1 ( SLC22A1 ), OCT2 ( SLC22A2 ), and OCT3 ( SLC22A3 ). All are members of the
SLC22A family of solute carrier (SLC) transporters, which includes the novel organic
cation transporters OCTN1 and OCTN2 ( SLC22A4 and SLC22A5 , discussed in de-
tail in Chapter 3) and the organic anion transporters OAT1-4 ( SLC22A6 , SLC22A7 ,
SLC22A8 , and SLC22A11 , discussed in detail in Chapter 4), as well as several trans-
porters that are less well characterized. The molecular identification of the organic
cation transporters (OCTs) has led to more detailed studies of the transport mecha-
nism, substrate specificity, and tissue distribution of these transporters, and to a greater
understanding of their roles in organic cation disposition and elimination.
2.2. STRUCTURAL-FUNCTIONAL CHARACTERISTICS
AND TRANSPORT MECHANISM
In terms of structural and functional characteristics, all three of the OCTs share
several common features: (1) a similar transmembrane topology, (2) a shared group
of preferred substrates, and (3) a common transport mechanism. 14 − 20 The OCTs also
share a common genomic structure of 11 coding exons. The genes encoding the three
OCTs are located in close proximity on human chromosome 6q26, and presumably
arose via gene duplication from a single ancestral OCT gene.
The predicted secondary structure of the OCTs, based on sequence or hydropathy
analysis, consists of 12 transmembrane domains (TMDs) with cytoplasmic amino