I.
Introduction
Opioids
analgesics produce analgesia at peripheral and central sites. However, the
principal target of action remains the central nervous system (CNS). The
presence of the blood brain barrier (BBB) presents a challenge for effective
delivery of analgesics to the CNS. In recent years, it has become evident that
a complex group of interacting cells constituting the BBB have other
properties, influencing solute transportation and metabolic activity, other
than offering an anatomical barrier to the free passage of drugs (Begley, 2004a). Many drugs, including opioids, which
are potentially effective at their site of action, may have a decreased effect
due to a failure to deliver them in sufficient amount to the CNS. The aims of
this review were multiple. Thus, to provide a comprehensive reading, before
describing how opioids may be delivered to brain, the characteristics of the
BBB will be described, as well as some specific conditions most frequently
encountered in clinical daily practice when using opioids, like cancer or
chronic pain conditions, able to modify BBB function.
II. Anatomy and physiology of BBB
The
function of the BBB is twofold. The BBB has either an anatomic and
neuroprotective function. A stable milieu is essential for CNS activity to
perform its complex integrative activity.
BBB enables the creation of a stable compartment of intracerebral
extracellular fluid, distinct from the systemic extracellular fluid. The
somatic extracellular fluid contains many substances at variable concentrations
that cannot be tolerated in the CNS, which operates in an extremely stable
background. The BBB has also a protective action against potentially damaging
neuroactive substances and other neurotrasmitters with highly variable changes
in systemic extracellular fluids, blocking their entry or actively transforming
by hydrolyzing and conjugating enzymes, and removing them from brain via active
efflux transporters. For example, amino acids present in high plasma
concentrations are potent excitatory neurotransmitters in CNS. A typical
example of metabolic function of the BBB is represented by the model of
successful treatment of ParkinsonÕs disease. L-Dopa crosses the BBB via a
neutral amino acid transporter and is then converted by dopa-decarboxylase to
biologically active dopamine (Neuwelt, 2004).
Furthermore, there is an enzymatic barrier at the cerebral endothelia, capable
of metabolizing drugs and nutrients, and include gamma-glutamyl transpeptidase,
alkaline phosphatase and decarboxylases. Finally, drug efflux transporters,
such as P-glycoprotein, are mainly present on the luminal membrane surface (see
below).
The
BBB is a thin, membraneous structure formed by the cerebral endothelial cells
of brain and spinal cord capillaries, astrocytes, basement membrane, pericytes,
and neurones in physical proximity to the endothelium. Endothelial cells are
connected by tight junctions produced by the interaction of transmembrane
proteins, which interact to impede free diffusion for polar solutes. Despite
the capability of endocytosis is lower in comparison with peripheral
endothelial cells, this mechanism is significant for transportation across BBB
of macromolecules, such as peptides and proteins.
Endothelial
cells express transport proteins in the two interfaces, in both sides
(bidirectional) or one side (unidirectional). Endothelial cells, adjacent
pericytes, and the end-feet of astroglia induce the tight junction formation,
the expression of transport proteins, and differentiation of cerebral
endothelium, and contribute to the proteins of the surrounding extracellular
matrix, which in turn influence the differentiation of the cells constituting
the BBB, also named neurovascular unit. The interaction of these junctional
proteins blocks free diffusion for polar solutes from blood. These
transmembraneous proteins include occludin, claudins, junctional adhesion
molecules, and membrane-associated guanylate kinase-like proteins (Persidsky et al, 2006).
Some
substances can be transported into the brain, and others out. As tight
junctions seal off the brain to polar solutes, endothelial cells are required
to maintain high level of expression of transport proteins for essential polar
metabolites to facilitate their efflux (Begley 2004b).
The endothelial cells forming BBB also exhibit a polarized expression of
transport proteins, so that the transport of some solutes can be facilitated in
either direction depending on the direction of gradient concentration. Finally,
perivascular macrophages and microglia are part of the BBB and contribute
differentiating and modulatory signals (Zenker et al,
2002).
A
similar barrier, the blood-cerebrospinal fluid barrier (B-CSF-B) is present in
the epithelium of the choroid plexus and circumventricular organs, although
these structures result to be more permeable. The total surface area of
circumventricular organs is smaller than that of the BBB and results to be less
efficient than expected to delivery substances, other than for several pharmacokinetic
considerations (Bickel et al, 2001). Choroid
plexus produces CSF and regulates the movement of solutes in a bidirectional
way, while circumventricular organs are fenestrated to allow a restricted
volume of extracellular fluid to rapidly equilibrate with plasma, the
composition resembling a plasma ultrafiltrate. Dendritic processes and receptors
on neurons within this area can interact with blood-borne solutes and their
nervous activity can be modulated. The cells forming the avascular arachnoid
membrane enveloping the whole CNS also possess tight junctions, that
effectively seal the paracellular diffusional pathway between these cells (Begley, 2004a). CSF drains proteins and other metabolites
from the interstitial fluid. The volume of CSF that leaves the CNS via
pseudolymphatic pathways may nearly equal the volume of CSF that leaves via
arachnoid granulations. Because of these blood-CNS barriers and the lack of a
true lymphatic vessels, the CNS is often considered immunologically privileged,
although a slow influx of white cells has been noted in some circumstances and
may subject to changes in disease states (see below) (Neuwelt,
2004).
III. Passage of drugs through the
BBB
Physicochemical
characteristics of drugs are determinant for passing BBB, the molecular weight
being between 150 and 500 Da and a log octanol-water partition coefficient between
0.5 and 6. Only the uncharged fraction of drugs partially ionized determines
the diffusion gradient for a passive diffusion across BBB.
The
ability of drugs to cross the BBB has long been recognized to be predicted by
molecular weight, degree of ionization, protein binding, and lipid solubility.
Some small solutes with high lipophilicity are observed to poorly penetrate the
BBB and show lower permeability into the brain than expected (Hamabe et al, 2006). In contrast, some substances may
have an even larger CNS entry, not commensurate with that predicted on the
basis of their lipid solubility penetration. These molecules, which are mainly
essential metabolites for the brain, are facilitated by a carrier-mediated or
energy-dependent concentrative mechanism entry dependent on specific proteins
inserted in the membranes of the capillary endothelial cells. Transport is
often asymmetric. Passive paracellular transport of hydrophilic compounds is
restricted by tight junctions between endothelial cells of the BBB (Fromm, 2004).
A
transport lipidic vector interacts with a cell surface receptor initiating
transcytosis. After tissue enzymes cleaves the peptide from its vector, the
free substance will be then available for interaction with its specific
receptor in brain cells (Bickel et al, 2001) or
converted into an active metabolite at their site of action (Bodor and Buchwald, 2003). Other than lipid
solubility, favouring CNS penetration, stable plasma concentration associated
with long half-life helps maintaining the diffusion gradient over an extended
period.
Other
than direct instillation of chemotherapeutic agents, spinal therapies are
increasingly used for chronic pain, both malignant and non-malignant. In
general, there is a positive correlation between the degree of water solubility
and both the spread of analgesia and adverse effects. Highly water-soluble
opioids like morphine administered intrathecally exhibit a greater degree of
rostral spread in comparison with lipophilic opioids like fentanyl, offering better
supraspinal analgesia and more extensive coverage (Cohen
and Dragovich, 2007).
Transmucosal
route is a viable and interesting possibility for the delivery of some drugs to
the brain. In fact olfactory neurons, surrounded by arachnoid membrane, containing
CSF, terminates penetrating the olfactory mucosa (Dale
et al, 2002). Alternately, nasally administered drugs are taken up by
the olfactory nerves and transported by retrograde axonal cytoplasmic flow back
into CSF (Begley, 2004a). Thus, CSF has direct
communication with olfactorial mucosa via perineuronal space, and drugs may
enter the CSF without restrictions usually linked to the BBB.
IV. BBB transporters
A
large number of transporters are present in the BBB, most of them being
designed to carry polar substances into the brain that would otherwise have
minimal access to the CNS. The large neutral aminoacid carrier is the transport
system that appears to accept the widest variety of substrates (Begley et ao, 2004a). All the observations regarding
the unpredictability of traditional factors influencing the drug passage
through the BBB may be partially explained by recent investigations regarding
membrane-bound drug transporters capable of actively pumping a variety of drugs
out of the CNS. Most of the BBB transporters are from the superfamily of
ATP-binding cassette (ABC) proteins, which mediate cellular extrusion of
substances with diverse structures.
The most characterized of the ABC transporters is the ABCB1 (MDR1,
P-glycoprotein) (P-gp). P-gp is a saturable transporting system systemically
expressed widely in several tissues, having a protective role and conferring
drug-resistance by impeding the delivery of therapeutic agents. Together with
xenobiotic-metabolizing enzymes, P-gp expression is believed to be an important
protective mechanism against potentially toxic xenobiotics. P-gp limits drug
entry as a result of its expression in enterocytes, hepatocytes, proximal tube
cells in the kidneys, and at BBB level. Thus, P-gp is an important component of
the BBB that limits accumulation of many compounds in brain via active flux
across the luminal membrane of capillary endothelium. P-gp is also expressed in
the spinal cord and choroids plexus (Dagenais et al,
2004). A reduction of this functional protein could lead to highly
increased brain distribution of P-gp substrates (Taylor,
2002). P-gp-knockout experiments have contributed significantly to
understanding of the importance of P-gp in limiting drug transfer to the brain.
Limited penetration through the BBB could be an obstacle to adequate drug
therapy, and a state of P-gp over expression may be one mechanism underlying
pharmaco-resistance.
P-gp
interacts with a diverse set of hydrophilic and amphiphatic compounds as well
as lipophilic compounds and confers resistance to tumor cells by extruding
cytotoxic natural product hydrophobic drugs using the energy of ATP hydrolysis.
Other complex interactions are known to occur with modulators of the multidrug
resistance phenotype (Sauna and Ambudkar, 2001).
P-gp acts as an energy-dependent efflux pump, which transports a wide array of
structurally divergent compounds, including chemotherapeutic agents, calcium
channel blockers, antiarrythmics, immunosuppressants, HIV preotease-inhibitors,
and many opioid analgesics, from the intracellular to the extracellular
compartment (Ambudkar et al, 1999). As the
system is saturable, various compounds can compete with each other, including
many drugs that currently in clinical use, such as quinidine, verapamil, and
ketokonazole. Some substances, like probenecid, cyclosporine and verapamil, may
inhibit the activity of these transporters and could improve delivery across
BBB (Neuwelt, 2004). P-gp inhibitors reverse
drug resistance in cancer patients and improve treatment outcome (Gottesman, 2002), although P-gp modulators might
increase toxicity to the CNS. Antisense approach showed a down regulation of
P-gp, which in turn, reduced the efflux of the compounds from the brain into
circulation (King et al, 2001).
V. Factors impairing BBB integrity
in cancer
Several
diseases may produce relevant changes in BBB, and transport of some specific
substances can be impaired (Neuwelt 2004). The
efficacy of BBB may decline with age, although it is not clearly demonstrated (Preston, 2001). The importance of P-gp was first
recognized in cancer cells, where it is responsible for the development of
resistance to cytotoxic agents. Brain tumors may affect BBB function due to
changes in microvessels morphology with some discontinuation and development of
fenestration (Schlageter et al, 1999). The
degree of BBB integrity is variable in the different areas of the tumor, and
these different permeabilities result in sharply reduced concentrations of
chemotherapeutic agents (Siegal and Zylber-Katz, 2002).
Moreover BBB integrity often recovers when the bulk of a tumor decrease with
treatment. Finally, some glial tumors demonstrated increased levels of P-gp (Neuwelt, 2004).
In
damaged brain tissue after traumatic injury, an increased BBB permeability to morphine
has been reported in the penumbra zone surrounding a focal mass lesion and in
apparently normal brain regions in patients with general brain swelling (Ederoth et al, 2003). Extravasation into the brain
through the BBB may be influenced by weak inflammatory stimuli such as pain, or
stronger stimuli such as infection and other immunological factors.
The
BBB compromise and cell extravasation with modulation by cytokines and
chemokines, are key events in the changes of BBB permeability. Corticosteroids
and other therapeutic agents decrease the passage of immune cells across the
BBB (Gasperini et al, 1998). Peripheral
inflammatory hyperalgesia has been found to produce an up-regulation P-gp in
BBB endothelial cells, restricting the passage of morphine across the BBB (Seelback et al, 2007). This information suggests that
pathophysiological states, such as inflammation and infection can impact drug
availability (McRae et al, 2003).
VI. Pain and BBB
Pain
is a complex phenomenon involving endocrine and immunological responses. The
immune response is characterized by the release of inflammatory mediators in
response to a stimulus and is typified by increased vascular permeability,
edema formation and leukocyte migration. Other kinins, prostaglandins, matrix metalloproteinases,
cellular adhesion molecules, excitatory peptides and aminoacids, numerous
cytochines, both excitatory and inhibitory, are involved in the immune response
when microglia, neurons, astroglia, perivascular cells are activated. Levels of
cytochine expression depend on the brain region. Chemokines recruit leukocytes
to the site of inflammation playing inflammatory and homeostatic roles.
Cytochines have also been shown to activate hypothalamic-pituitary-adrenal
(HPA) axis producing a stress cascade response down to corticosteroids, which
in turn modulate the expression of cytochines, chemiotaxis, and production of
inflammatory mediators (Wolka et al, 2003).
Inflammatory mediators have also been shown to alter receptor-mediated endocytic
reuptake at the BBB. Cytochines appear to play a role in BBB disruption,
increasing endothelial permeability due to loss of the tight junction proteins.
Adhesions of leukocytes induced by chemokines, produce similar damage. Mast
cell activation in response to hormonal stress also influences BBB
permeability. One consequence of BBB disruption has been shown to be increased
drug delivery to the brain. This altered delivery may be detrimental, resulting
in unexpected toxicity, or beneficial, resulting in improved therapeutic
outcome.
On
the other hand, the ability of the brain to secrete active peptides into
circulation may be a mechanism providing neurochemical links to peripheral
sites. Evidence suggests that BBB may be unidirectional, and able to secrete a
wide range of structurally diverse compounds from the brain to circulation.
Some cytokines, for example, do not pass into the brain to an appreciable
degree in normal condition when given intravenously. Yet, they are rapidly
excreted from the brain to the blood (King et al, 2001).
VII. Opioid passage through BBB
It
is well known that the doses of opioids needed for pain relief clinically vary
between individuals. The response to opioids depends on several factors,
including variable bioavailability, differences in pain mechanism, differences
in pharmacodynamics at the μ-receptor, in drug metabolism, and genetics (Mercadante and Portenoy, 2001). Recent studies
revealed that inherited differences in drug-metabolizing enzymes, opioid
receptors, and drug-transporters, might affect the effectiveness of opioid
drugs in individual patients (Klepstad et al, 2005).
Although there are many factors that can influence the
pharmacokinetics-pharmacodynamics of a drug, transport of opioids across the
BBB could be an important step in permitting opioids to exert a centrally
mediated analgesic effect. Many opioids have been identified as P-gp substrates
with variable degrees (Graff and Pollack, 2004,
Skorpen et al, 2008, Waldel et al, 2002, Kalvas et al, 2007).
Both
efflux and uptake carrier systems have been implicated in the transport of
opioid drugs. Transporter expression at the BBB has the potential to
significantly influence the clinical efficacy and safety of opioids, whose
major site of action lies within the CNS. The two major families of drug
transporters of relevance to opioid pharmacokinetics are the ABC superfamily of
efflux transporters, and the solute carrier (SLC) superfamily of influx
transporters. P-gp expression at the BBB is of particular importance to
opioids, regulating the access to their site of action and consequently
affecting efficacy. Opioid analgesics given systematically have limited
distribution into the brain because of their interaction with P-gp, with the
brain uptake and the antinociceptive effects of opioids being dependent on P-gp
function. Opioids activate P-gp ATPase, producing energy requisite for P-gp
transport. The relative dependence of opioids of P-gp is an important
determinant for opioid action. Among opioid analgesics there are some
differences in substrate specificity for P-gp. Morphine and fentanyl have been
found to activate P-gp ATPase in the brain capillary endothelial cell membranes
and showed higher analgesic potencies in P-gp-deficient mice suggesting that
their analgesic effects are considerably dependent on P-gp expression. In
contrast meperidine did not show ant-activating effect of P-gp ATPase (Hamabe et al, 2006).
Studies
have indicated that the presence of P-gp reduces both the magnitude and
duration of analgesia produced by morphine, methadone, and fentanyl, whereas
the analgesic efficacy of M6G and meperidine is less affected (Thompson et, 2002), suggesting that some opioids may
be weak substrates for P-gp. However, in another experiment assessing the
initial bran uptake, increased brain accumulation was demonstrated only for
morphine. It can be expected that the effect under steady-state conditions
would be more significant also for other opioids (Dagenais
et al, 2004). Factors interacting with P-gp functioning may alter the
response to opioids. Drugs that are not themselves substrates for P-gp but may
inhibit P-gp are a potential source of important drug interactions, allowing
the increased penetration into CNS of concomitant drugs. The inhibition of P-gp
results in substantial alteration of drug tissue availability of concomitantly
administered drugs, with unexpected more clinical effects, but also producing a
potential to cause adverse effects of those with a narrow safety margin.
Loperamide,
which has a prevalent peripheral effect, is a high affinity P-gp substrate that
is effectively pumped out of the CNS that pharmacologically effective
concentrations are not achieved in the brain, despite being a potent opioid (Wandel et al, 2002).
Morphine
is an effective analgesic, which requires high plasma concentrations to
penetrate to enter in small amount the BBB, due to its hydrophilicity. Data regarding modulation of P-gp
modulation are contrasting. The active efflux of morphine across the BBB has
been demonstrated, also producing a delay of the clinical effects (Mantione et al, 2005). But an acute inhibition of
P-gp did not affect pharmacokinetics of morphine in volunteers (Drewe et al, 2000). Individual differences in
morphine analgesia were negatively correlated with relative cortical P-gp
expression levels and basal P-gp ATP-ase activity (Hamabe
et al, 2005). This effect was not observed with high doses of morphine,
possibly due to the saturation of morphine-P-gp coupling, leading to the
increment of non-specific permeation across the BBB. Of interest, although
morphine injection may increase P-gp ATP-ase activity, this returns to the
basal level after elimination of substrate drug, suggesting that this mechanism
is not relevant for developing antinociceptive tolerance (Al-Shavi et al, 2003). However, other studies
supported that down regulation of P-gp enhanced both the potency and duration
of action of systemic morphine, and blocked the development of tolerance (King et al, 2001). Induction of P-gp may be one
mechanism involved in the development of morphine tolerance. Chronic morphine
exposure appeared to induce P-gp in rat brain, enhancing the morphine efflux
from the brain (Aquilante et al, 2000).
Down-regulation of P-gp enhanced both the potency and duration of action of
systemic morphine, and blocked the development of tolerance (King et al, 2001). On chronic administration the
up-regulated P-gp would be expected to result in lower brain concentration of
morphine and thereby exacerbating tolerance to the central analgesic effects (Mercier et al, 2007). It has also been suggested that
P-gp transport system may provide a mechanism of communication between the CNS
and the periphery throughout the secretion of peripherally acting peptides and
hormones. P-gp active transport of morphine out of the brain into circulation
could be crucial in providing a synergistic interaction between peripheral and
central opioid systems (King et al, 2001). In
MDR-1 knockout mice there was a two-fold increased net brain uptake of
morphine, lending support to the notion that P-gp may affect the brain morphine
disposition (Schinkel et al, 1996). Down
regulating P-gp expression with antisense reduced the brain to blood transport
of morphine and other opioids resulting in significantly enhanced systemic
morphine analgesia. However, analgesic analgesia of centrally administered
morphine decreased, suggesting that supraspinal analgesia depends on a
combination of central and peripheral mechanisms activated by morphine
transported from the brain to the blood. Similar effects were produced disrupting
the MDR1 gene (King et al, 2001).
M6G
is a metabolite of morphine that appears to have a greater analgesic potency
than morphine. M6G has a higher
potency when administered by intracerebroventricular route and produce a longer
antinociceptive effect than morphine. It is highly hydrophilic and has BBB
permeability 57 times lower than morphine. However the brain uptake rate is
only 32 times lower suggesting that an active transport mechanism might exist (Mantione et al, 2005). Although efflux transporters
act on M6G at the BBB, the probenecid-sensitive transporters seem to be not
involved in the brain efflux, as the ratio was unaltered when probenecid was
co-administered (Tumblad et al, 2005), and
possibly is trapped by other transporters (Bourasset
et al, 2006).
Chemical
lipidization may increase brain penetration of morphine. A lipophilic drug with
limited activity, able to penetrate the BBB, can be converted in an active
substance within CNS, and get more polar to be effectively retained in the CNS.
For example, in codeine, the hydroxyl groups of morphine are substituted, the
molecule increases lipid solubility and increases brain uptake. Codeine is
rapidly transported into the brain and quickly reached distribution equilibrium
with the same unbound concentrations in blood and brain. Therefore the influx
is identical to efflux, which suggests that only passive process participate in
codeine BBB transport (Xie and ammarlund-Udenaes, 2005).
Substituting acetyl groups to form dyacethylmorphine (heroin), it is possible
to substantially increase CNS penetration, providing an excellent example of
chemical manipulation. However, dyacethylmorphine is also rapidly metabolized
back to the parent drug, and this form, after the typical flash clinically
observed, prevalently interacts with opioid receptors. Morphine maintains CNS
levels, as it cannot easily back diffuse across the BBB.
Drugs
with high octanol-water partition ratios, like fentanyl, tend to have high
tissue/blood partition ratios. This is evidence for both inward and outward
vectors of transport relative to the microvascular lumen. At the BBB, P-gp
actively pumps a variety of lipophilic drugs away from the brain tissue, thus
reducing the tissue/blood partition ratio that would exist by passive diffusion
alone. The active p-gp-mediated extrusion of fentanyl, however, is overshadowed
by an active inward transport process, mediated by an unidentified transporter.
Moreover studies also showed that fentanyl may act as P-gp inhibitor (Hentorn et al, 1999).
Despite
a lower affinity to opioid receptor, oxycodone and morphine have a similar
potency. This observation is explained by the finding that oxycodone is
actively influxed at the BBB, in comparison with morphine and its metabolites,
and codeine. It has been shown that the influx clearance is 3-fold greater than
the efflux clearance, resulting in a higher concentration for oxycodone than
could be anticipated from plasma concentrations (Bolstrom
et al, 2006). The concentration of unbound oxycodone in brain ISF was
six times higher than that of morphine for the same unbound plasma
concentrations, meaning that the rate of transport of oxycodone is very high
compared with morphine (Bolstrom et al, 2008). This
is probably due to transport proteins with saturable mechanisms (Bolstrom et al, 2006). These transporters are
energy-dependent, proton-coupled antiporter (Okura et
al, 2008).
Methadone
is characterized by the large variability in response, which has been related
to the complex pharmacodynamics and pharmacokinetics, or activity of P-gp. Methadone
has been shown to be a substrate of P-gp, suggesting a possible role of this
efflux protein in methadoneÕs individual variability. P-gp in BBB greatly
limits the brain entry of (R) and (S) methadone to their central nervous system
acting sites (Wang et al, 2004). The
polymorphic expression of P-gp in BBB may represent a source of variation for
the access and effects of methadone in the brain. Oral methadone potency was
increased three fold in patients treated with a P-gp-inhibitor, valspodar (Rodriguez et al, 2004). Methadone dosage requirement
has been reported to be influenced by ABCB1 haplotypes in opioid dependent
subjects in methadone maintenance treatment (Persidsky
et al, 2006). This finding was not confirmed in a similar group of
patients (Coller et al, 2006), possibly for the
different dose used, which saturated P-gp (Crettol et
al, xxxx).
P-gp
was found to mediate brain to blood efflux transport of buprenorphine across
the BBB, at least in part. The use of inhibitors, such as cyclosporine A,
quinidine, and verapamil, enhanced uptake of buprenorphine by 1.5-fold (Suzuki et al, 2007).
The
potential exists for drug interactions to result during chronic opioid therapy
because of P-gp inhibition for other drugs. P-gp substrates may competitively
inhibit P-gp, resulting in an increased uptake of opioids into brain. For
example, cyclosporine and verapamil are both inhibitors and substrates for
P-gp, digoxin, loperamide, vincristine, and dexamathasone are substrates for
P-gp, whereas quinidine and ketoconazole are inhibitors but not substrates for
P-gp (Waldel et al, 2002). While P-gp-inducers
such as rifampicin and St JohnÕs wort cause a substantial increase in
withdrawal symptoms (Coller et al, 2006),
P-gp-inhibitors verapamil, quinidine, and probenecid have been shown to reduce
the efflux clearance of morphine (King et al, 2001,
Tumblad et al, 2005). Valspodar, an analogue of cyclosporine D, has been
developed for its high potency to reverse the resistance to chemotherapy of
cancer cells by inhibiting P-gp. However, in humans, where direct measurements
of changes in brain disposition of morphine and M6G were not possible, and
relied on peripheral blood measurements, the coadministration of valspodar with
morphine did not significantly affect the pharmacokinetic and pharmacodynamic
profile of morphine (Drewe et al, 2000). While
most inhibitors are not particularly potent at clinically concentrations, some
drugs, such as corticosteroids may reach concentrations that are high enough to
affect the distribution and clearance of opioids, such as morphine, methadone,
and fentanyl (Thompson et al, 2000).
P-gp-inhibition as a way of increasing
the concentrations of drugs in the brain and thus increasing the central
effects was tested in studies using loperamide. Loperamide, an opioid presumed
to not producing central effects, elicits potent centrally mediated opioid-like
effects and evidences increased brain accumulation in P-gp-deficient mice (Xie and Hammarlund-Udenaes, 1998). When administered
with quinidine, a known relatively selective P-gp-inhibitor, loperamide
produced respiratory depression, independently from the plasma concentration of
the drug (Begley, 2004b). Moreover, in P-gp
knockout mice, doses of loperamide that are normally without effect in wild
mice were lethal (Schinkel et al, 1996).
VIII. P-gp pharmacogenomics and opioids
Many
studies have increased our knowledge and understanding of how pharmacogenetics
can influence the opioid response and contribute to interpatient variability.
However, the importance of pharmacogenomics at present is at the level of
explaining variability in drug response and toxicity, and not necessarily its
immediate translation into clinical practice (Skorpen
et al, 2008). Drug transport is often the result of the concerted action
of efflux and uptake pumps located both in the basolateral and apical membranes
of epithelial cells. Polymorphisms affecting drug transporters are of interest
for opioid analgesia, as altered function or expression of transporters might
cause differences in the extracellular brain concentrations of opioids.
Although there are many transporters that theoretically could be involved in
transport of opioids, most studies have focused on P-gp.
P-gp
functions as a transmembrane efflux pump that translocates its substrates from
its intracellular domain to its extracellular domain. Given such an important
role of P-gp in the drug disposition process, it is not surprising to see
increasing focus on the role of polymorphisms in this transporter as a
potential determinant of interindividual variability in pharmacological
response. Differences in opioid potencies may also be due to structure-activity
relationship (Mercier et al, 2007).
The
ABCB1 gene encoding P-gp is highly polymorphic, with more than 50 single
nucleotide polymorphisms, and possesses the potential to affect the expression
and function of the transporter. Genetic or chemical disruption of P-gp has
been shown to enhance the antinociceptive and toxic effects of some opioids,
although the extent of this phenomenon has yet to be better understood. Genetic
polymorphisms of P-gp may affect opioid pharmacokinetics by changing the levels
of P-gp expression. Many polymorphisms have been identified in the ABCB1 gene
and several have been associated with differences in protein expression and
function (Skorpen et al, 2008).
Animal
and human studies have produced conflicting results regarding the functional
consequences of polymorphisms in terms of opioid activity, although there is
some evidence that the brain distribution of morphine, which is transported by
these systems with less efficiency than loperamide, may be affected by 3435
genotype. This polymorphism did not influence the pharmacodynamic effects of
methadone (Lotsch et al, 2006). No association
between morphine dose requirements and polymorphisms 2677G/A or 3435C>T was
found (Coulbault et al, 2006). However, highly
significant association between variability of pain relief and genotypes of the
3435C>T polymorphism was recently found (Campa et
al, 2008). The effect of haplotypes, meaning significant linkage
disequilibrium across ABCB1 gene, is more likely to predict P-gp expression and
function. For example, employing ABCB1 haplotypes, subjects for the wild-type
haplotypes required significant higher dose of methadone than heterozygous or
non-carriers, and carriers of AGCTT haplotype required lower doses compared
with non-carriers (Somogyi et al, 2007).
Similarly, the ABCB1 GG2677/CC3435 diplotype has been found to predict morphine
adverse effects than either of the two analyzed separately (Coulbault et al, 2006).
Genotypes
susceptible to fentanyl were associated with early decrease of respiration rate
as compared with resistant genotypes (Park et al, 2006).
Adverse effects were not correlated to 3435C>T genotype in morphine-treated
cancer patients (Campa et al, 2008).
The
hypothetical effects of two polymorphic genes, one involved in pharmacokinetics
(ABCB1, MDR1, encoding P-gp), and another involved in pharmacodynamics (OPRM1,
encoding for μ-opioid receptor), have been evaluated. Pain relief
variability was associated with both polymorphism, the single-nucleotide
polymorphism C3435T of ABCB1 and A80G of OPRM1, and combining the extreme
genotypes of both genes, the association between patient polymorphism and pain
relief improved (Campa et al, 2008). The
commonest adverse effects that limit dose titration are drowsiness and
confusion. The occurrence of these central adverse effects is the main reason
to switch from one opioid to another. In a study of markers of the need of
opioid switching in cancer patients with pain who poorly responded to morphine,
genetic variation in MDR-1 has been found to be independently associated with
moderate-severe drowsiness and confusion or hallucinations, with G2677T/A
showing the strongest association. Of interest, no differences were observed in
serum morphine levels between genotypes, reflecting the poor correlation
between serum and CNS levels f morphine (Ross et al,
2008).
The
discrepancies among the results of the various studies of ABCB1 genetic
polymorphisms or haplotypes on the function of P-gp variants include small
study population, lack of standardization for the determination of P-gp
expression, interethnic differences, and unknown roles of other transporters (Fromm, 2004).
Of
the multidrug resistance-associated proteins in the ABCC family, ABCC1, ABCC2,
and ABCC3 are the most likely to be involved in opioid transport and a number
of glucuronide conjugates (Somogyi et al, 2007).
Several polymorphisms have been identified, but functional consequences to the
transport of opioids have not been determined yet.
The
organic anion transporting popypeptides (SLCO) family consists of different
isoforms. SLCO1A2 is predominantly expressed in the brain capillary endothelial
cells, differently from SLCO1B3, which is almost expressed in the liver. The
identification of functionally relevant genetic polymorphisms warrants further
investigation (Somogyi et al, 2007).
IX. Conclusions
Different
models and experimental conditions have been used, including inhibition of
binding or transport of another substrate, use of non-specific inhibitors,
antinociceptive response without concurrent measurement of brain accumulation,
making it difficult to assess quantitatively the interaction of opioids with
P-gp. Moreover, other factors, such as plasma protein binding, affinity for
brain tissue, egress component, other peripheral sites, for example intestinal,
liver, and kidney P-gp, different metabolic genotypes, pharmacological
interactions, receptor polymorphisms, may also minimize the influence of BBB
P-gp functioning, which should be considered as a part of the complex framework
determining the final response to opioids in individuals.
The
polymorphisms that affect the response to opioids are likely to be complex and
multigenetic, with a number of alleles each making a modest contributes to the
overall phenotype. In addition, environmental and behavioural factors combine
with pharmacokinetic and pharmacodynamic factors. This information may help in
the development of an effective strategy for customization of opioid therapy.
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