DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 432

extracellular loops can possess two to seven glycosylation sites, while the intracel-
lular loops have various protein kinase A and C phosphorylation sites. 287 , 289 These
symporters couple the uphill movement of small peptides with the downhill movement
of protons across biological membranes via an inwardly directed electrochemi-
cal H + -gradient and a negative membrane potential. 291 - 293 Apart from transport-
ing sequence-independent di- and tripeptides, pharmacologically active peptidelike
drugs ( -lactam antibiotics, ACE inhibitors, and antiviral nucleoside analogs), neu-

ropeptides (carnosine, an endogenous dipeptide), and endogenous peptidomimetics
(5-aminolevulinic acid) are also transported by these PTs. 286 , 289 , 294 , 295 The brain, in-
cluding cerebral cortex, cerebellum, and choroid plexus, 296 , 297 also express peptide
transporters that are involved in uptake of substrates from the systemic circulation
and CSF into the brain cells. Furthermore, uptake by PTs of enzymatic degrada-
tion products of neuropeptides that may still be bioactive at the synapse has been
proposed. 296 - 298
Peptide transporter 1 (PEPT1, SLC15A1) was first cloned from a rabbit intesti-
nal cDNA library 299 and shown to have high capacity and low affinity for di- and
tripeptides. In mammals, this transporter is expressed primarily in the apical plasma
membrane of enterocytes in the intestine 300 and is responsible for the absorption of
small peptides arising from digestion of dietary proteins. 299

No Pept1 protein was

found in the rat brain. 301
Peptide transporter 2 (PEPT2, SLC15A2) was first cloned from a human kid-
ney cDNA library 302 and shown to have low capacity and high affinity for di- and
tripeptides. 303 PEPT2 protein is expressed in various tissues, including lung, mam-
mary gland, retina, and brain. 301 , 304 In the brain, Pept2 is expressed in rat cerebral
cortex but the physiological role of the peptide transporter in the cerebral cortex,
is yet to be seen. 297 Pept2 transcript has also been identified in rat astrocytes 304 , 305
and could contribute to brain glutathione metabolism by providing cysteinylglycine
derived from extracellular glutathione 298 or for removing neuroactive peptides such
as kyotorphin 306 from the extracellular fluid. At the rat choroid plexus, both protein
expression 307 and functional activity 308 have been assessed, and localization of the
transporter has been identified at the apical membranes of the choroidal epithelium
using immunofluorescent confocal microscopy. 309 However, since the BBB is imper-
meable to 5-aminolevulinic acid (5-ALA), the presence of this compound, which was
inhibited by

-amino-containing cephalosporins but not Pept1 inhibitors in the CSF,
could be attributed to expression of either Pept2 or other transporters at the basolat-
eral side of the choroidal epithelium. 307 In studies performed by Shu and co-workers,
there was a preferential uptake ( K m of GlySar was 59.6

M for apical and 1400

M for basolateral uptake) of the model dipeptide into primary culture of rat choroid
plexus epithelial cells. 309 Furthermore, plasma concentrations of 5-ALA were much
higher than those found in CSF, 307 suggesting the presence of an active transport
system for 5-ALA at the choroid plexus epithelium. 307 Taken together, PEPT2 may
have a role as an efflux pump for the effective removal of neuropeptides, peptides,
and peptidomimetics from CSF into the blood. Pharmacological inhibition of PEPT2
could maximize CNS penetration of therapeutic peptides that are substrates for this
transporter. 309