DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 424

where it is detected only in the meninges. 159 This differential temporal expression
suggests a yet undetermined role of this anion transporter during the development of
the CNS structures. 162 Murine Oat1 has also been detected in neurons of the cere-
bral cortex and hippocampus, as well as in the ependymal cell layer of the choroid
plexus. 163 Various studies have shown expression of OAT1 at the apical side of choroid
plexus epithelial cells. 160 , 162 , 164 This in turn suggests OAT1 involvement in removal
of anionic drugs and neurotransmitter metabolites such as vanillin mandelate from
the CSF to the blood across the CP. 160 , 162 , 164
Organic anion transporter 2 (Oat2; Slc22a7), cloned from rat liver and described
as novel liver transporter, 143 was characterized by Sekine and colleagues. 165 OAT2
protein is liver specific and is not expressed in the brain. 139 , 165 Only Oat2 mRNA has
been detected in rat choroid plexus. 92
Organic anion transporter 3 (Oat3; Slc22a7) was fist cloned from a rat brain
cDNA library. It is the most abundant OAT in the brain and is also expressed
in liver, kidney, lungs, and eye. 146 , 166 Human OAT3 cloned from the kidney 167 is
also highly expressed in the skeletal muscle and brain. 168 In rodent kidney, Oat3
is localized to the basolateral membrane of proximal tubules. 146 , 169 In the CNS,
immunochemical staining revealed basolateral 141 and faint luminal localization of
Oat3 in rat brain capillaries, 170 as well as apical membrane localization in rat 171
and human 164 choroid epithelial cells. Studies in Xenopus laevis oocyte express-
ing Oat3 have shown transport of PAH, estrone sulfate, taurocholate, ochratoxin,
benzylpenicillin, cimetidine, and ranitidine but not tetraethylammonium in a Na + -
independent manner. 140 , 146 , 171 Furthermore, benzylpenicillin transport from the CSF
was also Na + -independent and inhibited by PAH. Conversely, elimination of cime-
tidine from the CSF was inhibited by benzylpenicillin and PAH, but not by N 1 -
methylnicotinamide, a quaternary amine and typical substrate for organic cation
transporters. 172 , 173 Taken together, these results suggest that the organic anion trans-
port properties via the blood-brain and/or BCSF barrier are consistent with transport
by OAT3. In studies where PAH and homovanillic acid, a metabolite of dopamine,
was injected into the brain, rapid and saturable efflux from the brain was detected
via the BBB. 141 , 174 Furthermore, anionic metabolites of neurotransmitters such as
epinephrine, norepinephrine, dopamine, and serotonin potently inhibited the uptake
of estrone sulfate via rat Oat3-expressing oocyte, suggesting an involvement of Oat3
in the extrusion and elimination of endogenous organic anions from the brain via the
blood-brain and BSCF barrier. 146 In other studies where Oat3 gene was disrupted,

there was a significant decrease ( 75 %) in fluorescein uptake by murine choroid

plexus, but no change in fluorescein-labeled methotrexate uptake by the underlying
capillaries of the choroid plexus epithelium. 140 This suggests that Oat3 has apical
localization in the choroid plexus cells and that the basolateral exit is not affected
by Oat3 loss. Taken together, Oat3 appears to play a vital role in the entry step
of substrates into the choroid plexus, leading to elimination of substrates from the
CSF. 140
Organic anion transporter 4 (OAT4; SLC22A11) was cloned from human kidney
cDNA library and found to be expressed predominantly in the apical membranes
of proximal tubules 175

∼

of the kidney and placenta. 147 RT-PCR studies have also