Biomedical Engineering Reference
In-Depth Information
peptide transporter (PepT1) was cloned from rabbit intestine in the early 1990s.
21
Subsequently, the orthologs of rabbit PepT1 were identified from other species,
including humans.
22
The gene encoding human PepT1 (hPepT1) maps to human
chromosome 13q33-34 and consists of 23 exons. As predicted by hydropathy anal-
ysis, the membrane topology model of PepT1 suggests 12 transmembrane domains
(TMD) and a large extracellular loop between TMD 9 and 10 with the N- and C-
termini facing the cytosol.
21
,
23
The expression of PepT1 was found primarily in
small intestine, with low levels in the liver and kidney.
22
In the human GI tract,
hPepT1 appears to have higher expression levels in the duodenum than in jejunum
or ileum.
24
Immunohistochemical studies revealed that PepT1 protein is localized
predominantly to the apical microvillous plasma membrane of the absorptive ep-
ithelial cells in rat small intestine.
25
The uptake of PepT1 substrates (i.e., di- and
tripeptides or structurally related drugs) is mediated by a proton gradient and the
membrane potential at the apical surface of epithelial cells. Briefly, an inward pro-
ton gradient is established at the brush border membrane by the Na
+
/H
+
exchanger,
and then the influx of protons back into the epithelial cells is coupled by PepT1 to
transport its substrates, thus, the system is known as a proton-dependent cotransport
system.
26
PepT1 has generally been characterized as a low-affinity/high-capacity transporter
with a wide variety of compounds as substrates. Drug molecules transported by PepT1
include
-lactam antibiotics such as penicillins and cephalosporins,
27
angiotensin-
converting enzyme (ACE) inhibitors such as captopril, and the ester prodrugs enalapril
and fosinopril.
28
Prodrugs of acyclovir (e.g., valacyclovir) and L-dopa (e.g., L-dopa-
L-Phe) can also be recognized and transported by PepT1.
29
,
30
While conventional
approaches to enhancing the bioavailability of orally administered drugs focused on
the optimization of dissolution, solubility, and passive permeability of drugs, cou-
pling of active drugs (e.g., acyclovir and L-dopa) with an amino acid (e.g., Val or
Phe) to target PepT1 significantly improves the intestinal absorption of the drugs by
recognition and uptake via PepT1.
29
,
31
16.4.2. OATP-Mediated Absorptive Transport
Members of the OATP family that have been found in the human intestine and are rela-
tively well studied are OATP-A and OATP-B. OATP-A was originally cloned from the
human liver,
32
and its transcript is found predominantly in the blood-brain barrier in
cerebral capillary endothelial cells, and to a lesser extent in the intestine.
33
,
34
Although
immunohistochemical studies to identify the precise subcellular location of OATP-A
at intestinal brush border membrane have not provided an unequivocal conclusion at
the present time, some in vivo functional data suggest that OATP-A is localized at the
apical side of intestinal epithelial cells as an absorptive transporter.
35
The drugs trans-
ported by OATP-A include fexofenadine.
35
and saquinavir.
36
Using OATP-A cRNA-
injected
Xenopus laevis
oocytes, the affinity (
K
m
) between saquinavir and OATP-A
was characterized as 36.4
M,
36
suggesting that the impact of OATP-A on
intestinal transport of saquinavir after oral delivery is questionable since at typical
±
21.8
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