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

2005; Torres and Amara, 2007). These transporters
also may be involved in the pathogenesis of neuropsychiatric
disorders, including Alzheimer’s and
Parkinson’s diseases (Shigeri et al., 2004; Sotnikova
et al., 2006). Transporters that are non-neuronal also
may be potential drug targets, e.g., cholesterol transporters
in cardiovascular disease, nucleoside transporters
in cancers, glucose transporters in metabolic
syndromes, and Na + -H + antiporters in hypertension
(Bobulescu et al., 2005; Kidambi and Patel, 2008;
Pascual et al., 2004; Rader, 2006; Zhang et al., 2007).
Drug Resistance. Membrane transporters play critical
roles in the development of resistance to anticancer
drugs, antiviral agents, and anticonvulsants. Drug resistance,
particularly to cytotoxic drugs, generally occurs
by multiple mechanisms, two of which involve membrane
transporters. Decreased uptake of drugs such as
folate antagonists, nucleoside analogs, and platinum
complexes, is mediated by reduced expression of influx
transporters required for these drugs to access the
tumor. Enhanced efflux of hydrophobic drugs is one of
the most frequently encountered mechanisms of antitumor
resistance in cellular assays of resistance. For
example, P-glycoprotein is overexpressed in tumor cells
after exposure to cytotoxic anticancer agents ( Lin and
Yamazaki, 2003; Leslie et al., 2005; Szakacs et al.,
2006). P-glycoprotein pumps out the anticancer drugs,
rendering cells resistant to their cytotoxic effects. Other
efflux transporters, including breast cancer resistance
protein (BCRP), and multidrug resistance-associated
proteins (MRPs), also have been implicated in resistance
to anticancer drugs (Clarke et al., 2002; Toyoda et
al., 2008). The over-expression of multidrug resistance
protein 4 (MRP4) is associated with resistance to antiviral
nucleoside analogs (Imaoka et al., 2006; Schuetz
et al., 1999).
MEMBRANE TRANSPORTERS AND
ADVERSE DRUG RESPONSES
Through import and export mechanisms, transporters
ultimately control the exposure of cells to chemical carcinogens,
environmental toxins, and drugs. Thus, transporters
play crucial roles in the cellular toxicities of
these agents. Transporter-mediated adverse drug
responses generally can be classified into three categories
(Figure 5–3).
Transporters expressed in the liver and kidney,
as well as metabolic enzymes, are key determinants
of drug exposure in the circulating blood, thereby
affecting exposure, and hence toxicity, in all organs
(Figure 5–3, top panel) (Mizuno et al., 2003). For
example, after oral administration of an HMG-CoA
reductase inhibitor (e.g., pravastatin), the efficient
first-pass hepatic uptake of the drug by the organic
anion-transporting polypeptide OATP1B1 maximizes
the effects of such drugs on hepatic HMG-CoA reductase.
Uptake by OATP1B1 also minimizes the escape
of these drugs into the systemic circulation, where
they can cause adverse responses such as skeletal
muscle myopathy.
Transporters in toxicological target organs or at barriers to
such organs affect exposure of the target organs to drugs.
Transporters expressed in tissues that may be targets for drug toxicity
(e.g., brain) or in barriers to such tissues (e.g., the blood-brain
barrier [BBB]) can tightly control local drug concentrations and
thus control the exposure of these tissues to the drug (Figure 5–3,
middle panel). For example, to restrict the penetration of compounds
into the brain, endothelial cells in the BBB are closely
linked by tight junctions, and some efflux transporters are
expressed on the blood-facing (luminal) side. The importance of
the ABC transporter multidrug resistance protein (ABCB1, MDR1;
P-glycoprotein, P-gp) in the BBB has been demonstrated in mdr1a
knockout mice (Schinkel et al., 1994). The brain concentrations of
many P-glycoprotein substrates, such as digoxin, used in the
treatment of heart failure (Chapter 28), and cyclosporin A
(Chapter 35), an immunosuppressant, are increased dramatically in
mdr1a(–/–) mice, whereas their plasma concentrations are not
changed significantly.
Another example of transporter control of drug exposure can
be seen in the interactions of loperamide and quinidine. Loperamide
is a peripheral opioid used in the treatment of diarrhea and is a substrate
of P-glycoprotein. Co-administration of loperamide and the
potent P-glycoprotein inhibitor quinidine results in significant respiratory
depression, an adverse response to the loperamide
(Sadeque et al., 2000). Because plasma concentrations of loperamide
are not changed in the presence of quinidine, it has been
suggested that quinidine inhibits P-glycoprotein in the BBB, resulting
in an increased exposure of the CNS to loperamide and bringing
about the respiratory depression. Inhibition of P-glycoproteinmediated
efflux in the BBB thus would cause an increase in the concentration
of substrates in the CNS and potentiate adverse effects.
The case of oseltamivir (the antiviral drug TAMIFLU) provides
an example that dysfunction of an active barrier may cause a CNS
effect. Abnormal behavior appears to be a rare adverse reaction of
oseltamivir. Oseltamivir and its active form, Ro64-0802, undergo
active efflux across the BBB by P-glycoprotein, organic anion transporter
3 (OAT3), and multidrug resistance-associated protein 4
(MRP4) (Ose et al., 2009). Decreased activities of these transporters
at the BBB caused by concomitant drugs, ontogenetic and genetic
factors, or disease may enhance the CNS exposure to oseltamivir
and Ro64-0802, contributing to an adverse effect on the CNS.
Drug-induced toxicity sometimes is caused by the concentrative
tissue distribution mediated by influx transporters. For example,
biguanides (e.g., metformin and phenformin), widely used as oral
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CHAPTER 5
MEMBRANE TRANSPORTERS AND DRUG RESPONSE