ORGANIC CATION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 15

Electrophysiological studies using Xenopus laevis oocytes microinjected with
OCT1, OCT2, or OCT3 cRNA show directly that transport of organic cations by
OCTs is electrogenic (i.e., addition of substrate to the extracellular media results
in inward currents). 4 , 10 , 23 − 29 OCT activity is insensitive to changes in the Na +
gradient. 17 Transport of weak bases by OCTs has also been shown to be sensi-
tive to extracellular pH; however, this is explained by the decrease in fractional
ionization of the substrate at high pH and does not indicate that transport of or-
ganic cations is driven by proton exchange. 30 OCT transport can also occur by
cation-cation exchange. Preloading OCT1-injected X. laevis oocytes with unlabeled
TEA enhances uptake of [ 3 H]MPP + , 26 and similar results have been found for

OCT2. 31

2.3. SUBSTRATE SELECTIVITY

Common substrates of all OCTs include low-molecular-weight relatively hydrophilic
organic cations such as the prototypical cation TEA, the neurotoxin MPP + , and the
endogenous compound N -methylnicotinamide (NMN). 18 , 20 , 32 Several clinically im-
portant drugs have been shown to interact with all of the OCTs, including the antidia-
betic drug metformin, 18 , 33 and the peptic ulcer drug famotidine, 34 demonstrating the
broad potential for influence of OCTs on drug disposition and drug action. Figure 2.3
shows the structures of several compounds that interact with OCTs. Table 2.1 lists
known substrates and inhibitors of human OCTs. 18 , 20 , 30 , 32 − 38
Included among OCT substrates are endogenous compounds such as the bio-
genic amine neurotransmitters. Dopamine, epinephrine, norepinephrine, histamine,
and serotonin have all been shown to interact with one or more OCT isoforms. 20 , 32
Of particular interest in this regard is OCT3, which was cloned as the extraneu-
ronal monoamine transporter (EMT) and is thought to comprise the uptake-2 system
of catecholamine transport, which aids in clearance of catecholamines in extraneu-
ronal tissues. 39 Despite the particular preference of OCT3 for biogenic amines, it
is suggested that all three of the cloned OCT transporters combine to contribute to
extraneuronal clearance of amine neurotransmitters. 32 , 40
Although the OCT family shows broad overlap in substrate specificity, there are
examples of relatively isoform-specific substrates and inhibitors. Examples include
corticosterone, which has approximately 40-fold greater affinity than Oct1 for rat
Oct2, and conversely, mepiperphenidol and O -methylisoprenaline, which show a 70-
fold greater affinity for rOct1 than for rOct2. 23 OCT3 appears to have the most
unique substrate selectivity among the OCT family, with a preference for endogenous
monoamines such as dopamine and norepinephrine.
Notably, although most known substrates of the OCTs are cations, some OCT
substrates are anionic or neutral compounds at physiological pH. For example, the
anions prostaglandin E 2 and prostaglandin F 2 α

have been shown to be substrates for

both OCT1 and OCT2, 41 and the neutral steroid

-estradiol interacts with OCT3 with
high affinity. 39 Thus, a net positive charge does not appear to be an absolute require-
ment for interaction with the OCTs.

β