DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION I
GENERAL PRINCIPLES
In the intestine, MRP3 can mediate the intestinal absorption in conjunction
with uptake transporters. MRP3 mediates sinusoidal efflux
in the liver, decreasing the efficacy of the biliary excretion from the
blood, and excretion of intracellularly formed metabolites, particularly,
glucuronide conjugates. Thus, dysfunction of MRP3 results in
a shortening of the elimination half-life (Kitamura et al., 2008;
Zelcer et al., 2005).
MRP4 substrates also can be transported by the OAT family
transporters (OAT1 and OAT3) on the basolateral membrane of the
epithelial cells in the kidney. MRP4 is involved in the directional
transport in conjunction with OAT1 and/or OAT3 in the kidney
(Hasegawa et al., 2007). The rate-limiting process in renal tubular
secretion is likely the uptake process at the basolateral surface.
Dysfunction of MRP4 enhances the renal concentration, but has limited
impact on the blood concentration.
GENETIC VARIATION IN MEMBRANE
TRANSPORTERS: IMPLICATIONS FOR
CLINICAL DRUG RESPONSE
Inherited defects in membrane transport have been
known for many years, and the genes associated with
several inherited disorders of membrane transport have
been identified [Tables 5–2 (SLC) and 5–3 (ABC)].
Reports of polymorphisms in membrane transporters
that play a role in drug response have appeared only
recently, but the field is growing rapidly. Cellular studies
have focused on genetic variation in only a few
drug transporters, but progress has been made in characterizing
the functional impact of variants in these
transporters, including characterization of the effects
of single-nucleotide polymorphisms (SNPs) (Burman
et al., 2004; Gray et al., 2004; Leabman et al., 2003;
Osato et al., 2003; Shu et al., 2003; see also Chapter 7).
The clinical impact of membrane transporter variants
on drug response has been studied only recently.
Clinical studies have focused on a limited number of
transporters, relating genetic variation in membrane
transporters to drug disposition and response. For
example, two common SNPs in SLCO1B1 (OATP1B1)
have been associated with elevated plasma levels of
pravastatin, a widely used drug for the treatment of
hypercholesterolemia (Mwinyi et al., 2004; Niemi et
al., 2004) (see Chapter 31). Recent studies using
genome-wide association methods have determined
that genetic variants in SLCO1B1 (OATP1B1) predispose
patients to risk for muscle toxicity associated with
use of simvastatin (Search Collaborative Group, 2008).
Other studies indicate that genetic variants in transporters
in the SLC22A family associate with variation
in renal clearance and response to various drugs including
the anti-diabetic drug, metformin (Shu et al., 2007;
Song et al., 2008; Wang et al., 2008). Further genetic
variants in MRP2 and MRP4 have been associated with
various drug related phenotypes (Han et al., 2007; Kiser
et al., 2008; Naesens et al., 2006). Chapter 7 presents a
more thorough discussion of the effects of genetic variation
in membrane transporters on drug disposition and
response.
TRANSPORTERS INVOLVED
IN PHARMACOKINETICS
Drug transporters play a prominent role in pharmacokinetics
(Figure 5–1). Transporters in the liver and kidney
have important roles in removal of drugs from the blood
and hence in metabolism and excretion.
Hepatic Transporters
Hepatic uptake of organic anions (e.g., drugs,
leukotrienes, and bilirubin), cations, and bile salts is
mediated by SLC-type transporters in the basolateral
(sinusoidal) membrane of hepatocytes: OATPs (SLCO)
(Abe et al., 1999; Konig et al., 2000) and OATs (SLC22)
(Sekine et al., 1998), OCTs (SLC22) (Koepsell, 1998),
and NTCP (SLC10A1) (Hagenbuch et al., 1991),
respectively. These transporters mediate uptake by either
facilitated or secondary active mechanisms.
ABC transporters such as MRP2, MDR1, BCRP,
BSEP, and MDR2 in the bile canalicular membrane of
hepatocytes mediate the efflux (excretion) of drugs and
their metabolites, bile salts, and phospholipids against
a steep concentration gradient from liver to bile. This
primary active transport is driven by ATP hydrolysis.
Moreover, SLC type transporter, MATE1 (SLC47A1),
is also located on the canalicular membrane of hepatocytes.
As a cation-proton antiporter, it works as an
efflux transporter of organic cations, though its role in
the biliary excretion of drugs has not been clearly
demonstrated so far.
Some ABC transporters are also present in the
basolateral membrane of hepatocytes and may play a
role in the efflux of drugs back into the blood, although
their physiological role remains to be elucidated. Drug
uptake followed by metabolism and excretion in the
liver is a major determinant of the systemic clearance of
many drugs. Since clearance ultimately determines systemic
blood levels, transporters in the liver play key
roles in setting drug levels.
Vectorial transport of drugs from the circulating
blood to the bile using an uptake transporter (OATP
family) and an efflux transporter (MRP2) is important