DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 425

shown OAT4 mRNA in the choroid plexus epithelial cells 176 and brain microvessel
endothelial cells. 90 Transport by OAT4 which is bidirectional and Na + independent is
believed to be involved in reabsorption and secretion of prostaglandins, 177 estrone sul-
fate, ochratoxin A, 147 , 175 and other anionic substrates through the kidney and choroid
plexus, as well as excretion of toxic substrates from the fetal into maternal circulation
in the placenta. 147
Organic anion transporter 5 (Oat5; Slc22a19) was cloned from rat kidney cDNA
library and expressed predominantly at the apical membranes of proximal tubules of
the kidney. 178 Organic anion transporter 6 (Oat6; Slc22a20), on the other hand, was
cloned from mouse olfactory mucosa. 153 Neither Oat5 nor Oat6 are expressed in the

brain. 148 , 153
Renal-specific transporter (RST, SLC22A12), the mouse homolog of human urate
transporter 1 (URAT1), was cloned from mouse kidney. 144 Both human URAT1 and
mouse RST are localized on the apical (brush border) side of the renal proximal tubules
and are believed to be involved in the reabsorption of urate in the kidney. 179 , 180 Al-
though human URAT1 is expressed primarily in the kidney, the mouse homolog pro-
tein is highly expressed in the choroid plexus and brain capillary-enriched fraction. 180
Depolarization of membrane voltage stimulates the transport activity of this protein.
As suggested by Breen and co-workers, there are membrane voltage-sensitive ex-
cretion mechanisms for organic anion and fluorescein-labeled methotrexate in the
choroid plexus. Hence, mouse RST, in coordination with OAT3, could potentially
play a role in the extrusion of anionic metabolites of neurotransmitters from the
CNS. 181

14.3.4. Organic Cation Transporter Family

Organic molecules with transient or permanent net positive charge are referred to as
organic cations and have decreased ability to permeate biological membranes pas-
sively. Therefore, entry of cationic molecules across cell membranes requires active
transport. Agents varying from (1) endogenous compounds such as acetylcholine,
choline, thiamine, N 1 -methylnicotinamide, and creatinine, to (2) the biogenic amines
dopamine, serotonin, epinephrine, and norepinephrine, to (3) therapeutic agents such
as cimetidine, metformin, acyclovir, memantine, and quinidine are among the host
of compounds transported by the organic cation transporter system. 182 - 186 There are
also several weak bases, uncharged, and even anionic compounds that are transported
by this system. 187
Organic cation transporters (OCTs), found in various mammalian tissues as well
as lower eukaryotes, bacteria, and plants, 188 have been divided into two major groups:
oligospecific and polyspecific transporters. Oligospecific transporters facilitate the
transport of a single main substrate or molecules with closely related structures
and include the Na + -cotransporters for neurotransmitters, high-affinity transporters
for thiamine, and vesicular and plasma membrane cotransporters for choline. 183
Polyspecific transporters , on the other hand, mediate the transport of organic cations
with different molecular structures 186 , 189 , 190 and belong to a large transporter fam-
ily of OCTs, or family 22 of solute carrier superfamily (SLC22A). 191 Two distinct