DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 422

uptake of centrally active opioids. The transport of these substrates by OATP-A was
inhibited by the opiate antagonists naloxone and naltrindole as well as the -opioid

receptor agonist Tyr-D-Ala-Gly- N -methyl-Phe-glycinol and the endogenous peptide
Leu-enkephalin. 120 Other OATP isoforms that have also been detected in human
brain include OATP-B, 121 OATP-D, 122 OATP-E, 123 and OATP-F. 124 Using Xenopus
laevis oocytes and transfected human embryonic kidney cells (HEK293), previous
studies have shown that these OATPs may be involved in the transport of both thera-
peutic agents and endogenous substrates including bromosulfophthalein, pravastatin,
sulfated steroids (i.e., estrone 3-sulfate), prostaglandins (PGE 1 , PGE 2 , PGF 2 ) and
thyroid hormones. 121 - 126 However, the exact cellular localization of these isoforms
in the human brain has yet to be elucidated. In addition, mRNA expression of human
prostaglandin transporter (hPGT), a member of the SLC21A family of transporters, 119
has been reported in both adult and fetal brain tissue. 127 Although the expression of
hPGT in human brain tissue suggests that it may be involved in the CNS transport of
prostaglandins, further studies are required to elucidate the exact role of this trans-
porter in the brain.

Rodent Oatp Isoforms Similar to human OATPs, several Oatp isoforms have been
detected in tissue isolated from rodent brain. Gene and protein expression of Oatp1
has been observed in neonatal rat choroid plexus. 128 Although fluorescence confo-
cal microscopy studies have shown that this transporter is localized intracellularly
in neonatal rats, this same method has shown that Oatp1 is localized primarily to
the apical surface of choroid plexus epithelial cells in adult rats. 128 The localization
of this transporter suggests that it may be involved in regulating the brain perme-
ation of therapeutic agents such as estradiol 17

-D-glucuronide, 129 fexofenadine, 130
and D-penicillamine(2,5)-enkephalin. 120 Expression of other Oatp isoforms (e.g.,
Oatp2, Oatp3, Oatp14) has been reported in brain capillary-enriched fractions and/or
brain capillary endothelial cells as well as in choroid plexus epithelial cells. 92 , 131 - 133
These Oatps may be involved in the brain transport of substrates such as digoxin, 134
fexofenadine, 130 D-penicillamine(2,5)-enkephalin, 135 estrone 3-sulfate, 131

and thy-

roid hormones. 132
In terms of the brain parenchyma, a few studies have reported the neuronal ex-
pression of both Oatp3 and Oatp9. 129 , 136 Neuronal expression of Oatp9 is interesting
since many of its substrates are involved in inflammatory signaling and regulation
(i.e., prostaglandins, leukotriene C4), suggesting that this transporter may play an
important role in transporting signals to target cells during brain inflammation. 129 In
addition, Gao and colleagues (2000) observed that Oatp2 immunoreactivity did not
colocalize with GFAP, which implies that astrocytes do not express Oatp2. 120 Overall,
the cellular compartments of the brain parenchyma remain poorly characterized for
the expression of Oatp family members.
Immunoblot analysis has detected the expression of prostaglandin transporter
(rPGT), an Slc21a family member, in cultured rat cerebral endothelial cells, astro-
cytes, pericytes, and choroid plexus epithelial cells. 137 Immunocytochemical analysis
detected strong rPGT immunoreactivity in the supraoptic and paraventricular nuclei
of the hypothalamus as well as in the ependymal cell layer of the third ventricle and