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

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SECTION I
GENERAL PRINCIPLES
increase GABA levels in the synaptic cleft of GABAergic neurons
by inhibiting the reuptake of GABA. GAT3 is the target for the
nipecotic acid derivatives that are anticonvulsants.
SLC6A2 (NET). NET (617 amino acids) is found in central and
peripheral nervous tissues as well as in adrenal chromaffin tissue
(Hahn and Blakely, 2007). In the brain, NET co-localizes with
neuronal markers, consistent with a role in reuptake of monoamine
neurotransmitters. The transporter functions in the Na + -dependent
reuptake of norepinephrine and dopamine and as a higher-capacity
norepinephrine channel. A major role of NET is to limit the synaptic
dwell time of norepinephrine and to terminate its actions, salvaging
norepinephrine for subsequent repackaging. NET knockout mice
exhibit a prolonged synaptic half-life of norepinephrine (Xu et al.,
2000). Ultimately, through its reuptake function, NET participates in
the regulation of many neurological functions, including memory
and mood. NET serves as a drug target; the antidepressant
desipramine is considered a selective inhibitor of NET. Other drugs
that interact with NET include other tricyclic antidepressants and
cocaine. Orthostatic intolerance, a rare familial disorder characterized
by an abnormal blood pressure and heart rate response to
changes in posture, has been associated with a mutation in NET.
SLC6A3 (DAT). DAT is located primarily in the brain in dopaminergic
neurons. Although present on presynaptic neurons at the neurosynapatic
junction, DAT is also present in abundance along the neurons,
away from the synaptic cleft. This distribution suggests that DAT may
play a role in clearance of excess dopamine in the vicinity of neurons.
The primary function of DAT is the reuptake dopamine, terminating
its actions, although DAT also weakly interacts with norepinephrine.
Physiologically, DAT is involved in the various functions that are
attributed to the dopaminergic system, including mood, behavior,
reward, and cognition. The half-life of dopamine in the extracellular
spaces of the brain is prolonged considerably in DAT knockout mice
(Uhl, 2003), which are hyperactive and have sleep disorders. Drugs
that interact with DAT include cocaine and its analogs, amphetamines,
and the neurotoxin MPTP.
SLC6A4 (SERT). SERT is located in peripheral tissues and in the
brain along extrasynaptic axonal membranes (Chen et al., 2004;
Olivier et al., 2000). SERT clearly plays a role in the reuptake and
clearance of serotonin in the brain. Like the other SLC6A family
members, SERT transports its substrates in an Na + -dependent
fashion and is dependent on Cl – and possibly on the countertransport
of K + . Substrates of SERT include serotonin (5-HT), various
tryptamine derivatives, and neurotoxins such as 3,4-methylenedioxymethamphetamine
(MDMA; ecstasy) and fenfluramine. The
serotonin transporter has been one of the most widely studied proteins
in the human genome. First, it is the specific target of the antidepressants
in the selective serotonin reuptake inhibitor class (e.g.,
fluoxetine and paroxetine) and one of several targets of tricyclic antidepressants
(e.g., amitriptyline). Further, because of the important
role of serotonin in neurological function and behavior, genetic variants
of SERT have been associated with an array of behavioral and
neurological disorders. In particular, a common promoter region
variant that alters the length of the upstream region of SLC6A4 has
been the subject of many studies (Hahn and Blakely, 2007). The
short form of the variant results in a reduced rate of transcription of
SERT in comparison with the long form. These differences in the
rates of transcription alter the quantity of mRNA and, ultimately, the
expression and activity of SERT. The short form has been associated
with a variety of neuropsychiatric disorders (Lesch et al., 1996). The
precise mechanism by which a reduced activity of SERT, caused by
either a genetic variant or an antidepressant, ultimately affects behavior,
including depression, is not known.
BLOOD-BRAIN BARRIER AND
BLOOD-CSF BARRIER
Drugs acting in the CNS have to cross the BBB or blood-
CSF barrier. These two barriers are formed by brain capillary
endothelial cells and epithelial cells of the choroid
plexus, respectively. These are not static anatomical barriers
but dynamic ones in which efflux transporters play
a role (Begley and Brightman, 2003; Sun et al., 2003).
P-glycoprotein is a well-characterized efflux transporter
that extrudes its substrate drugs on the luminal membrane
of the brain capillary endothelial cells into the
blood, thereby, limiting the brain penetration. Thus,
recognition by P-glycoprotein as a substrate is a major
disadvantage for drugs used to treat CNS diseases.
In addition to P-glycoprotein, there is accumulating evidence
for the roles of BCRP and MRP4 in limiting the brain penetration of
drugs at the BBB (Belinsky et al., 2007; Breedveld, et al., 2005;
Enokizono et al., 2007; Leggas et al., 2004; Ose et al., 2009).
Furthermore, because of overlapped substrate specificities of
P-glycoprotein and BCRP, they act as active barrier cooperatively in
the BBB (Enokizono et al., 2008). Thus, dysfunction of both
P-glycoprotein and BCRP exhibits synergy on the increase in the
brain-to-plasma concentration ratio of the common substrates compared
with that observed when either P-glycoprotein or BCRP is
dysfunctional (Oostendorp et al., 2009; Polli et al., 2009).
The transporters involved in the efflux of organic anions from
the CNS are being identified in the BBB and the blood-CSF barrier
and include the members of organic anion transporting polypeptide
(OATP1A4 and OATP1A5) and organic anion transporter (OAT3)
families (Kikuchi et al., 2004; Mori et al., 2003). They mediate the
uptake of organic compounds such as β-lactam antibiotics, statins,
p-aminohippurate, H 2
receptor antagonists, and bile acids on the
plasma membrane facing the brain-CSF in the net efflux across the
endothelial and epithelial cells. The transporters mediating the efflux
on the membranes that face the blood, have not been fully elucidated
both in the BBB and blood-CSF barrier. MRP4 has been shown to
mediate luminal efflux in the directional transport on an anionic
drug, Ro64-0802 (an active form of oseltamivir), across the BBB in
which the abluminal uptake is mediated by OAT3 (Ose et al., 2009).
Members of the organic anion transporting polypeptide family also
mediate uptake from the blood on the plasma membrane facing
blood. Further clarification of influx and efflux transporters in the
barriers will enable delivery of CNS drugs efficiently into the brain
while avoiding undesirable CNS side effects and help to define the
mechanisms of drug-drug interactions and interindividual differences
in the therapeutic CNS effects.