Biomedical Engineering Reference
In-Depth Information
either hepatic uptake or efflux transporters. The nomenclature, substrate specificity,
driving force(s) for transport, and clinical significance with respect to disease states
and/or drug interactions are summarized. Current information regarding transport
protein trafficking, regulation, and the potential role of hepatic transport proteins in
drug-induced hepatotoxicity is discussed. One of the greatest challenges in studying
hepatobiliary drug transport is selecting the right model system(s) and tools to an-
swer the relevant questions. An overview of approaches currently in use and under
development is provided. As scientific knowledge advances in this field, new tech-
niques and tools, and more sophisticated models are anticipated to aid in unraveling
the complexities of hepatic drug transport and exploiting these processes to achieve
desirable therapeutic outcomes.
13.2. HEPATIC UPTAKE TRANSPORT PROTEINS
The solute carrier (
SLC
) gene family, containing the
SLC10
and
SLC22
subfamilies,
together with the
SLCO
gene family represent the predominant transport proteins
that have been shown to mediate hepatic uptake of xenobiotics across the sinusoidal
hepatocyte membrane (see Figure 13.1). The previous and currently approved nomen-
clature for these uptake transporters that reside on the hepatic basolateral membrane,
and example substrates, are included in Table 13.1.
NTCP
(SLC10A1)
The Na
+
-taurocholate cotransporting polypeptide (NTCP),
which is expressed exclusively in liver, mediates sodium-dependent bile salt uptake
in human liver against a typical 5- to 10-fold concentration gradient and with a 2 : 1
sodium-to-taurocholate (TC) stoichiometry. NTCP accounts for an estimated 80% of
total hepatic uptake of conjugated bile acids.
279
Although the substrate specificity
of NTCP appears oriented primarily to bile acids, this protein also transports the
cholephilic compounds bromosulfophthalein (BSP) and estrone 3-sulfate.
280
More-
over, NTCP recently has been demonstrated to contribute to the hepatic uptake of
rosuvastatin.
281
In rats, Ntcp also has been reported to transport thyroid hormones
3
and the mushroom toxin
-amanitin (a cyclic octapeptide).
4
These findings indicate
that NTCP substrate specificity extends beyond bile acids and structurally related
compounds. Investigation of polymorphisms in NTCP, as reported by Ho et al.,
279
revealed that this transport protein exhibits a region that is critical and specific for
bile acid substrate recognition. Indeed, one NTCP variant displayed nearly complete
loss of bile acid transport but fully functional transport of estrone sulfate. Interest-
ingly, NTCP also was found to transport certain drugs when covalently bound to
taurocholate (i.e., chlorambucil-taurocholate).
5
OATPs
(SLCO;
Previously
, SLC21A)
The family of organic anion transporting
polypeptides (OATPs) plays an essential role in hepatic drug uptake. OATPs often
appear to be rate limiting in the hepatobiliary clearance of drugs, thus controlling
the hepatic elimination and/or oral bioavailability of various compounds. OATPs are
characterized by broad and overlapping substrate specificity and display affinity for
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