Biomedical Engineering Reference
In-Depth Information
on data generated by Kobayashi et al.
11
Human OAT2 has 79% sequence identity to
its rat ortholog Oat2,
10
but differences in substrate specificity and even membrane
localization (liver vs. kidney) exist.
14
,
15
Detection of mRNA for two additional OAT
transporters (originally referred to as OAT4 and OAT5) with exclusive expression in
liver has been reported
10
; however, the substrate specificity of these isoforms (gene
products
SLC22A9, SLC22A10
16
) remains to be elucidated. It should be noted that
the latter gene products are different from OAT4 (
SLC22A11
, expressed in placenta
and kidney) and mouse Oat5 (
SLC22A19
, expressed in kidney).
OCTs
(SLC22A)
Organic cation transporters (OCTs) are electrogenic uniporters that
mediate transport of primarily small (type I) cations in an Na
+
-independent fashion,
although transport of anionic (e.g., prostaglandins
17
) and uncharged compounds also
has been observed (see ref. 18 and references therein). Human OCT1 (
SLC22A1
;
expressed exclusively in liver
288
) and OCT3 (
SLC22A3
; broader tissue distribution)
are the isoforms expressed at the sinusoidal membrane of the hepatocyte. In addition
to small cationic model substrates, various marketed drugs, including the antivirals
acyclovir and ganciclovir, as well as the H
2
-receptor antagonists famotidine and
ranitidine have been identified as OCT1 substrates (see Table 13.1). Substrates for
OCT3 appear to be more limited to endogenous substances and neurotransmitters.
13.3. HEPATIC EFFLUX TRANSPORT PROTEINS
Hepatic excretion of xenobiotics from the liver may occur across the basolateral
membrane into sinusoidal blood, or across the canalicular (apical) membrane into bile
which flows through fine tubular canals between adjacent liver cells (see Figure 13.1).
Lists of substrates for human hepatic export proteins are provided in Table 13.2.
13.3.1. Canalicular Transport Proteins
Canalicular transport proteins, responsible for the hepatic excretion of drugs and
metabolites, belong to the ATP-binding cassette (ABC) family of transport proteins
which mediate ATP-dependent transfer of solutes. Canalicular transport proteins for
drugs and metabolites include P-glycoprotein (MDR1,
ABCB1
), the multidrug resis-
tance protein 3 (MDR3,
ABCB4
), the bile salt export pump (BSEP,
ABCB11
), the
multidrug resistance-associated protein (MRP2,
ABCC2
), and breast cancer resis-
tance protein (BCRP,
ABCG2
).
P-glycoprotein
(
MDR1
, ABCB1)
P-glycoprotein (Pgp) was first identified over
three decades ago in multidrug-resistant (MDR) tumor cells.
20
Pgp represents the
most widely studied ABC transport protein and is responsible for biliary excre-
tion of bulky hydrophobic and cationic substrates: chemotherapeutic agents (e.g.,
daunorubicin, doxorubicin, etoposide, paclitaxel, vinblastine, vincristine), cardiac
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