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

Membrane Transporters and
Drug Response
Kathleen M. Giacomini and
Yuichi Sugiyama
Transporters are membrane proteins that are present in all
organisms. These proteins control the influx of essential
nutrients and ions and the efflux of cellular waste, environmental
toxins, drugs, and other xenobiotics. Consistent
with their critical roles in cellular homeostasis, ~2000
genes in the human genome, ~7% of the total number of
genes, code for transporters or transporter-related proteins.
The functions of membrane transporters may be
facilitated (equilibrative, not requiring energy) or active
(requiring energy). In considering the transport of drugs,
pharmacologists generally focus on transporters from two
major superfamilies, ABC (ATP binding cassette) and
SLC (solute carrier) transporters.
Most ABC proteins are primary active transporters,
which rely on ATP hydrolysis to actively pump
their substrates across membranes. There are 49 known
genes for ABC proteins that can be grouped into seven
subclasses or families (ABCA to ABCG) (Borst and
Elferink, 2002). Among the best recognized transporters
in the ABC superfamily are P-glycoprotein (Pgp,
encoded by ABCB1, also termed MDR1) and the
cystic fibrosis transmembrane regulator (CFTR,
encoded by ABCC7).
The SLC superfamily includes genes that encode
facilitated transporters and ion-coupled secondary
active transporters that reside in various cell membranes.
Forty-eight SLC families with ~315 transporters
have been identified in the human genome (Hediger,
2004). Many serve as drug targets or in drug absorption
and disposition. Widely recognized SLC transporters
include the serotonin (5-HT) and dopamine transporters
(SERT, encoded by SLC6A4; DAT, encoded by
SLC6A3).
Analysis of physical chemical evidence suggests
that the involvement of transporters in the passage of
drugs across biological membranes may be more the
rule than the exception (Dobson and Kell, 2008). Drugtransporting
proteins operate in pharmacokinetic and
pharmacodynamic pathways, including pathways
involved in both therapeutic and adverse effects
(Figure 5–1).
MEMBRANE TRANSPORTERS IN
THERAPEUTIC DRUG RESPONSES
Pharmacokinetics. Transporters that are important in
pharmacokinetics generally are located in intestinal,
renal, and hepatic epithelia, where they function in
the selective absorption and elimination of endogenous
substances and xenobiotics, including drugs
(Ciarimboli, 2008; El-Sheikh et al., 2008; Shitara et al.,
2005; Srimaroeng et al., 2008). Transporters work in
concert with drug-metabolizing enzymes to eliminate
drugs and their metabolites (Figure 5–2). In addition,
transporters in various cell types mediate tissue-specific
drug distribution (drug targeting). Conversely, transporters
also may serve as protective barriers to particular
organs and cell types. Access of solutes to several tissues
such as the brain and testes is restricted by a capillary
endothelial barrier (e.g., the blood-brain barrier), and
the efflux transporters in these barrier endothelia may
limit penetration of drugs. For example, P-glycoprotein
in the blood-brain barrier protects the central nervous
system (CNS) from a variety of structurally diverse
drugs through its efflux mechanisms. Many of the transporters
that are relevant to drug response control the
tissue distribution as well as the absorption and elimination
of drugs.
Pharmacodynamics: Transporters as Drug Targets.
Membrane transporters are the targets of many
clinically used drugs. For example, neurotransmitter