DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 423

in the choroid plexus. 137 The prototypical substrate of rPGT is prostaglandin E2 138 ;
however, functional studies examining rPGT-mediated transport mechanisms in the
brain have not been undertaken.

14.3.3. Organic Anion Transporter Family

Organic anions (i.e., drugs, toxins, as well as endogenous and exogenous molecules)
that are sulfated or glucuronidated by phase II metabolism bear transient or perma-
nent negative charge at physiological pH. Such molecules are generally membrane
impermeable and are transported by the organic anion transport system. In the kid-
ney, organic anions are secreted by the proximal renal tubules into the urine for
elimination. This secretion is divided into two processes: (1) uptake of organic anions
from the peritubular blood plasma into the renal tubular cells through the basolat-
eral membrane, and (2) release of organic anions into the tubule lumen through the
apical brush border membrane. 139 Apart from the kidney, organic anion transport
system is also found in the brain, including the brain capillaries, choroid plexus,
and brain parenchyma. 7 , 140 Their expression in the choroid plexus and BBB, in hand
with evidence that steroid hormones, neurotransmitter, and their metabolites, such as
17

-estradiol) and homovanillic acid (from
dopamine), are substrates for organic anion transporters suggest that these transporters
regulate the composition of brain by controlling the flux of xenobiotics from CSF and
ECF into blood. 141
Organic anion transporters (OATs) belong to family 22 of the solute carrier su-
perfamily (SLC22A). 142 OATs are expressed primarily in epithelial tissues, (i.e., the
kidney and liver) but also in placenta, small intestine, choroid plexus, and brain
microvasculature that transport xenobiotics. 143 - 148 Currently, the OAT family com-
prises OAT1, 149 − 151 OAT2, 143 OAT3, 145 , 146 OAT4, 147 OAT5, 152 OAT6, 153 and renal-
specific transporter (RST). 144 OATs are categorized into three classes based on their
energy requirements: (1) Na + -dependent OATs, (2) Na + -independent facilitators or
exchangers, and (3) active OATs that require ATP. Na + -dependent OATs have a nar-
row substrate specificity and play a major role in the reabsorption of essential anionic
substrates into the proximal renal tubules. Na + -independent and active OATs, on the
other hand, possess broad substrate specificity and are involved in the secretion of
organic anions in kidney, liver, and brain. 7 , 154
Organic anion transporter 1 (Oat1, Slc22a6) is a transporter abundant in the
brain and was first cloned from rat and mouse and described as novel kidney
transporter. 149 - 151 Human OAT1 is highly localized at the basolateral membrane of
renal proximal tubular cells. 155 One of the hallmarks of this transporter is its ability to
exchange extracellular organic anions such as PAH for an intracellular dicarboxylate
(

-estradiol-D-17 -glucuronide (from 17

-ketoglutarate). 150 Here, uptake of PAH is coupled indirectly to Na + /dicarboxylate
transport and is tertiary active. 156 , 157 With respect to localization, OAT1/Oat1 is also
weakly expressed in the brain, 150 , 158 - 160 placenta, skeletal muscle, 158 and liver. 161
In mouse CNS (choroid plexus, dura mater, root ganglions, and spinal cord), Oat1
mRNA expression is highest at the embryonic stage and decreases toward adulthood,