drugs transporters
DESCRIPTION
importance of membrane transporters in the field of pharmacologyTRANSCRIPT
Prepared by
Alaa Ibrahim Assistant lecturer of clinical pharmacology
Under supervision of
Pro.Dr. Sohair El MenshawyProf. of clinical Pharmacology
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1- Introduction
2- Types of Transporters
3- Structure of Transporters
4- Mechanism of Action Of Transporters
5- Regulation of Transporter Expression
6- Physiological & Pharmacological role of
Transporters
7- Novel Approaches To Bypass Drug
Transporters
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The basic mechanisms involved in solute
transport across biological membranes include
passive diffusion, facilitated diffusion, and
active transport
Active transport can be further subdivided into
primary and secondary active transport.
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Mechanism of
membrane
permeation
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SECONDARY ACTIVE TRANSPORTER
PRIMARY ACTIVE TRANSPORTER
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Secondary active transport ( co-transport):
uses energy to transport molecules across a
membrane. In contrast to primary active transport,
there is no direct coupling of ATP; instead,
the electrochemical potential difference created by
pumping ions out of the cell is used.
The two main forms of this are
1- antiport: Na+\ Ca++ exchanger
2- symport: glucose symporter which co-
transports one glucose molecule into the cell for
every two Na+
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Types of 2ry Active Transporters
II- Symbort
( co-transport)
III- Antiport
( exchange)
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Types of Membrane Transporters
2000 genes in the human genome (7% of the total number of genes) code for transporters or transporter-related proteins.
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 substrates across membranes
The SLC superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters
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Transporters
ABC (ATP binding cassette)
49 known genes for ABC proteins that can be grouped into 7 subclasses or families (ABCA to ABCG)
the best recognized in the ABC superfamily are P-glycoprotein (P-gp, encoded by ABCB1, also termed MDR1) and the cystic fibrosis transmembrane regulator (CFTR).
48 SLC families with 315transporters have been identified in the human genome
Many serve as drug targets or in drug absorption and disposition
Widely recognized SLCtransporters include the serotonin (5-HT) and dopamine transporters (SERT, encoded by SLC6A4; DAT, encoded by SLC6A3).
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Structure of ABC Transporters
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The common feature of all ABC transporters is that they
consist of two distinct domains, the transmembrane
domain (TMD) and the nucleotide-binding domain
(NBD).
The TMD, also known as membrane-spanning domain
(MSD) or integral membrane (IM) domain, consists
of alpha helices, embedded in the membrane bilayer.
It recognizes a variety of substrates and undergoes
conformational changes to transport the substrate across
the membrane.
The sequence and architecture of TMDs is variable,
reflecting the chemical diversity of substrates that can be
translocated.11/18/2012 11Transporters
The NBD or ATP-binding cassette (ABC) domain, on the
other hand, is located in the cytoplasm and has a highly
conserved sequence.
The NBD is the site for ATP binding.
In most exporters, the N-terminal transmembrane
domain and the C-terminal ABC domains are fused as
a single polypeptide chain, arranged as TMD-NBD-
TMD-NBD.
Importers have an inverted organization, that is, NBD-
TMD-NBD-TMD, where the ABC domain is N-terminal
whereas the TMD is C-terminal
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Structure of ABC Transporters
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Structure of ABC Transporters
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Some ABC transporters have additional
regulatory class of proteins.
In particular, importers have a high-
affinity binding protein (BP) that specifically
associates with the substrate in the periplasm
for delivery to the appropriate ABC transporter
Exporters do not have the binding protein but
have an intracellular domain (ICD) that joins the
membrane-spanning helices and the ABC
domain.
The ICD is believed to be responsible for
communication between the TMD and NBD
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The structural architecture of ABC transporters
consists minimally of two TMDs and two ABCs.
Most exporters, such as in the multidrug
exporter are made up of homodimer consisting
of two half transporters
A full transporter is often required to gain
functionality
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ABC transporters are active transporters, they
require energy in the form of (ATP) to translocate
substrates across cell membranes. These
proteins harness the energy of ATP binding
and/or hydrolysis to drive conformational
changes in the transmembrane domain
(TMD) and consequently transports molecules.
Both ABC importers and exporters have a
common mechanism in transporting substrates
because of the similarities in their structures.
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In this model, the substrate binding site alternates
between outward- and inward-facing
conformations. The relative binding affinities of
the two conformations for the substrate largely
determines the net direction of transport.
For importers, since translocation is directed
from the periplasm to the cytoplasm, then the
outward-facing conformation will have higher
binding affinity for substrate. In contrast, the
substrate binding affinity in exporters will be
greater in the inward-facing conformation.
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This model presents two principal conformations
of the NBDs: formation of a closed dimer upon
binding two ATP molecules and dissociation to
an open dimer facilitated by ATP hydrolysis and
release of inorganic phosphate (Pi)
and adenosine diphosphate (ADP). Switching
between the open and closed dimer
conformations induces conformational changes
in the TMD resulting in substrate translocation
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Regulating the distribution and bioavailability of drugs
The removal of toxic metabolites and xenobioticsfrom cells into urine, bile, and the intestinal lumen
The transport of compounds out of the brain across the blood–brain barrier
Protection of hematopoietic stem cells from toxins
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Regulation of Transporter
Expression
Transcription of transporter mRNAs changes in
response to drug treatment and
pathophysiological conditions, resulting in induction or down regulation.
Recent studies have described important roles of
type II nuclear receptors, which form
heterodimers with the 9-cis-retinoic acid receptor
(RXR), in regulating drug-metabolizing enzymes
and transporters
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Such receptors include pregnane X receptor (
PXR), constitutive androstane receptor (CAR) ,farnesoid X receptor (FXR)& PPARα (peroxisome proliferator-activated receptor α)and retinoic acid receptor (RAR)
These are ligand-activated nuclear receptors that,
as heterodimers with RXR, bind specific elements in
the enhancer regions of target genes.
There is an overlap of substrates between
CYP3A4 and P-glycoprotein, and PXR mediates
coinduction of CYP3A4 and P-glycoprotein,
supporting their synergetic cooperation in
efficient detoxification
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Role of Transporters in Drug Absorption
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Various transporters are expressed in the brush-border membranes of intestinal epithelial cells involved in the efficient absorption of nutrients or endogenous compounds.
The influx transporters expressed in the gut improve drug absorption
Example: PEPT1, ASBT, OATP-B, OATP-D & OATP-E
PEPT1 mediates the transport of peptide-like drugs such as β-lactam antibiotics, ACEIsinhibitors and the dipeptide-like anticancer drug bestatin
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However efflux transporters, such as P-gp, MRP2,
or BCRP, are expressed on the brush-border
membrane of enterocytes and excrete their substrates
into the lumen, resulting in limitation of net
absorption
Active secretion of absorbed drug is now becoming
recognized as a significant factor in oral drug
bioavailability
P-gp affects the absorption of many drugs because of
its broad substrate specificity
The intestinal P-gp content correlates with the AUC
after oral administration of digoxin, a P-gp
substrate
Active secretion of absorbed drug is now
becoming recognized as a significant factor
in oral drug bioavailability
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Schematic
of role of
P-gp
intestinal
disposition
of
substrate.
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A report involving a patient undergoing a small
bowel transplant demonstrated that plasma conc. of
oral tacrolimus, a substrate of both P-gp and
CYP3A4, correlated well with the mRNA
expression of intestinal MDR1, but not CYP3A4
These results suggest that intestinal P-gp, rather than
CYP3A4, is a good probe to predict intraindividual
variations in tacrolimus pharmacokinetics.
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BCRP is a member of the ABC transporter family has only one ATP-binding cassette and six transmembrane domains, suggesting that BCRP is a half-transporter, which may function as a homo- or heterodimer.
BCRP plays a role in the secretion topotecan
When both topotecan, a substrate of BCRP, and GF120918, an inhibitor of both BCRP and P-gp, were administered orally, the bioavailability of topotecan was increased in P-gp-deficient mice (over 6-fold) compared with mice given vehicle alone
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BCRP is expressed not only in the intestine, but also
in the bile canalicular membrane and placenta .Thus,
treatment with GF120918 reduced the plasma
clearance and hepatobiliary excretion of topotecan .
Furthermore, in pregnant GF120918-treated, P-gp-
deficient mice, the fetal penetration of topotecan was
2-fold higher than that in pregnant mice given
vehicle alone.
These results indicate that BCRP plays an important
role in protecting the fetus from topotecan.
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Hepatic uptake of organic anions (e.g., drugs, LTs and
bilirubin), cations, and bile salts is mediated by SLC-type
transporters in the basolateral (sinusoidal) membrane of
hepatocytes:
1- OATPs (SLCO) and OATs (SLC22) for anions
2- OCTs and NTCP (SLC10A1) for cations & bile salts
This uptake either by 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
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VECTORIAL TRANSPORT11
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Vectorial transport of drugs from the circulating
blood to the bile using an uptake transporter
(OATP family) and an efflux transporter
(MRP2) is important for determining drug
exposure in the circulating blood and liver.
Different examples illustrate the importance of
vectorial transport in determining drug exposure
in blood & liver:
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1- HMG-CoA Reductase
Inhibitors:
Statins are cholesterol-lowering agents
that reversibly inhibit HMG-CoA reductase
enzyme
inhibit cholesterol biosynthesis mainly in
the liver ( the main target), while exposure
of extrahepatic cells in smooth muscle to
these drugs may cause adverse effects
Pravastatin, fluvastatin, cerivastatin,
atorvastatin, rosuvastatin are given in a
biologically active open-acid form
(relatively hydrophilic and have low
membrane permeability)
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However, most of the statins in the acid form are substrates of uptake transporters, so they are taken up efficiently by the liverand undergo enterohepatic circulation
So, hepatic uptake transporters such as OATP1B1 and efflux transporters such as MRP2 act cooperatively to produce vectorial transcellular transport of bisubstrates in the liver
The efficient first pass hepatic uptake of statins by OATP1B1 after their oral administration helps to exert the pharmacological effect and also minimizesthe escape of drug molecules into the circulating blood limiting systemic adverse effects
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2- Temocapril is an ACE inhibitor Its active metabolite, temocaprilat, is
excreted both in the bile and in the urine whereas other ACE inhibitors are excreted mainly via the kidney.
The special feature of temocapril among ACE inhibitors is that the plasma concentrationof temocaprilat remains relatively unchangedeven in patients with renal failure.
Temocaprilat is a bisubstrate of the OATP family and MRP2, whereas other ACE inhibitors are not good substrates of MRP2
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Taking these findings into consideration, the
affinity for MRP2 may dominate in
determining the biliary excretion of any
series of ACE inhibitors.
Drugs that are excreted into both the bile
and urine to the same degree thus are
expected to exhibit minimum interindividual
differences in their pharmacokinetics.
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3-Irinotecan (CPT-11): is a potent anticancer drug, but late-onset
gastrointestinal toxic effects, such as severe
diarrhea, make it difficult to use CPT-11
safely.
After intravenous administration, CPT-11 is
converted to SN-38, an active metabolite, by
carboxy esterase. SN-38 is subsequently
conjugated with glucuronic acid in the liver.
SN-38 and SN-38 glucuronide are then
excreted into the bile by MRP2.
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Some studies have shown that the inhibition
of MRP2-mediated biliary excretion of SN-38
and its glucuronide by coadministration of
probenecid reduces the drug induced
diarrhea, at least in rats.
It is expected that this agent will be used
clinically to prevent toxicity. Approaches
using intentional drug-drug interactions
(positive drug interactions) like this case
may become more important in the future
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4- Troglitazone:A thiazolidinedione insulin-sensitizing agent
for the treatment of NIDDM
Was withdrawn from the market because of
liver toxicity . the mechanism underlying this
troglitazone-associated hepatotoxicity is at
present unclear, but it has been suggested
that a cholestatic mechanism is involved
Troglitazone and, to a much greater extent
troglitazone sulfate, the main troglitazone
metabolite eliminated into bile, competitively
inhibit ATP-dependent taurocholate transport
via BSEP
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This inhibition of the hepatobiliary export of bile salts by troglitazone and troglitazone sulfate may lead to a drug-induced intrahepatic cholestasispossibly contributing to their hepatotoxicity
Cholestasis induced by some drugs is mediated, at least in part, by inhibition of BSEP, resulting in intracellular accumulation of cytotoxic bile salts. For examples: cyclosporine, rifampicin,glibenclamide & the cholestatic estrogenmetabolite
One should consider the possibility that drugs which inhibit BSEP may cause cholestasis
The evaluation of BSEP inhibition will play an important role in the identification of compounds that could be a potential cause of cholestasis.
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During the past decade, molecular studies have identified and characterized the renal transporters that play a role in drugelimination, toxicity and response.
we now can describe the overall secretory pathways for organic cations and their molecular and functional characteristics
Our understanding of organic anion transport has progressed in a similar fashion.
In some cases, transporters that are considered organic anion or organic cation transporters have dual specificity for anions and cations
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The OCT family of proteins is involved in
the uptake of organic cations into the
liver or kidney from blood. OCT1 and
OCT2 are expressed in epithelial cells of
the kidney, liver, and intestine, and appear
to be localized to the basolateral
membranes of the cells
These transporters mediate the uptake of
a variety of organic cations, such as
dopamine, choline, 1-methyl-4-
phenylpyridinium (MPP+), N1-
methylnicotinamide, TEA, and cimetidine
ranitidine, metformin, procainamide, and
N-acetylprocainamide11/18/2012 49Transporters
Organic cations cross the basolateral
membrane by three distinct transporters in
the SLC family 22 (SCL22): OCT1
(SLC22A1), OCT2 (SLC22A2), and OCT3
(SLC22A3).
Organic cations are transported across this
membrane down their electrochemical
gradient (–70 mV).
Transport of organic cations from cell to
tubular lumen across the apical membrane
occurs via an electroneutral proton–
organic cation exchange mechanism11/18/2012 50Transporters
Transporters assigned to the apical membrane are in the SLC22 family and termed novel organic cation transporters (OCTNs). In humans, these include OCTN1 (SLC22A4) and OCTN2 (SLC22A5).
These bifunctional transporters are involved not only in organic cation secretion but also in carnitine reabsorption.
OCT2 play a housekeeping role in neurons, taking up only excess concentrations of neurotransmitters.
OCT2 also involved in recycling of neurotransmitters by taking up breakdownproducts, which in turn enter monoamine
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The primary function of organic anion transporters is the removal of xenobiotics(include weak acidic drugs e.g. pravastatin, captopril, pencillins & toxins)
Two primary transporters on basolateralmembrane mediate the flux of organic anions from intestinal fluid to tubular cell : OAT1( SLC22A6) & OAT3 ( SLC22A8)
organic anions are transported across the basolateral membrane against an electrochemical gradient in exchange with intracellular α-ketoglutarate, which moves down its concentration gradient
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The mechanism responsible for the apical
membrane transport of organic anions
from tubule cell cytosol to tubular lumen
remains controversial
Some studies suggest that OAT4 may
serve as the luminal membrane
transporter for organic anions
Other transporters that may play a role in
transport across the apical membrane
include MRP2 and MRP4,multidrug-
resistance transporters in the ATP binding
cassette family C (ABCC).
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DRUG ACTION IN THE BRAIN
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• Transporters involved in the neuronal reuptake of the neurotransmitters and the regulation of their levels in the synaptic cleft belong to two major superfamilies, SLC1 and SLC6
• Transporters in both families play roles in reuptake of γ-aminobutyric acid (GABA), glutamate, and the monoamine neurotransmitters NA, 5-HT, and dopamine. These transporters may serve as pharmacologic targets for neuropsychiatric drugs.
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Transporters
• SLC6 family members in the brain involved in the reuptake of neurotransmitters into presynaptic neurons include the NA transporters (NET, SLC6A2), the dopamine transporter (DAT, SLC6A3), the serotonin transporter (SERT, SLC6A4), and several GABA reuptake transporters (GAT1, GAT2, and GAT3)
• The SLC6A family regulate the concentrations and dwell times of neurotransmitters in the synaptic cleft
• The extent of transmitter uptake also influences subsequent vesicular storage of transmitters.
• The transporters can function in the reverse direction.
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Transporters
SLC6A1 (GAT1), SLC6A11 (GAT3), and SLC6A13 (GAT2).
• GAT1 is the most important GABA transporter in the brain, expressed in GABAergic neurons and found largely on presynaptic neurons
• GAT3 is found only in the brain, largely in glialcells. GAT2 is found in peripheral tissues, including the kidney and liver, and within the CNS in the choroid plexus and meninges
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Transporters
• GAT1, GAT2, and GAT3 are approximately 50%identical in amino acid sequence
• The presence of GAT2 in the choroid plexus and its absence in presynaptic neurons suggest that this transporter may play a primary role in maintaining the homeostasis of GABA in the CSF.
• GAT1 and GAT3 are drug targets.• GAT1 is the target of the antiepileptic drug
tiagabine, which acts to 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.
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Transporters
• SLC6A2 (NET):• is found in central and peripheral nervous tissues
as well as in adrenal chromaffin tissue
• A major role of NET is to limit the synaptic dwell
time of NA and to terminate its actions, salvaging
NA for subsequent repackaging.
• 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
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Transporters
• SLC6A3 (DAT)DAT is located primarily in the brain in
dopaminergic neurons present mainly on presynaptic neurons at the neurosynapaticjunction & also present along the neurons, awayfrom the synaptic cleft.
The primary function of DAT is the reuptakedopamine, terminating its actions
DAT is involved in functions like mood, behavior, reward, and cognition
Drugs that interact with DAT include cocaine, amphetamines, and the neurotoxin MPTP
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Transporters
• SLC6A4 (SERT)SERT is located in peripheral tissues and in the
brain along extrasynaptic axonal membranes
SERT clearly plays a role in the reuptake and
clearance of serotonin in the brain
Substrates of SERT :
1- 5-HT
2- Tryptamine derivatives
3- 3,4-methylene-dioxymethamphetamine
(MDMA; ecstasy) neurotoxin
4- Fenfluramine
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Transporters
• The serotonin transporter has been one of the most widely studied proteins in the human genome
WHY ?
1- It is the specific target of the antidepressants in the selective serotonin reuptake inhibitor class SSRI
(e.g., fluoxetine and paroxetine)
2- One of several targets of tricyclicantidepressants TCA (e.g., amitriptyline)
3- The important role of 5-HT in neurological function and behavior, genetic variants of SERT have been associated with many behavioral and neurological disorders
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Transporters
• Membrane transporters play a critical role in the development of resistance to
1- anticancer drugs,2- antimicrobial agents
3- anticonvulsants. • N.B) P-glycoprotein is overexpressed in
tumor cells after exposure to cytotoxicanticancer agents
• P-glycoprotein pumps out the anticancer drugs
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Transporters
• Other transporters, have been implicated in
resistance to anticancer drugs include:
1- Breast cancer resistance protein (BCRP)
2- The organic anion transporters
3- several nucleoside transporters
• N.B) The overexpression of multidrug-resistance
protein 4 (MRP4) is associated with resistance
to antiviral nucleoside analogs
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Transporters
• Tumors arising from tissues where MDR1\P-gp
is highly expressed show intrinsic resistance to
different chemotherapeutic agents , although
acquired resistance is often correlated with an
increased expression of MDR1\P-gp
Inhibition of P-gp represents a promising approach for
treatment of multidrug-resistant tumors
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Transporters
I- Reversal agents:
They are also called as chemosensitizers as
they inhibit P-gp efflux of drugs and increase
the absorption of drugs intracellularly so these
agents may be co-administered with
therapeutic agent as competitive inhibitors.
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Reversal agents for P-gp as per the
generation:
A) First-generation agents
These agents had their own pharmacological action.
These agents were used in high dose as they were not
selective to inhibit P-gp so they resulted into high
toxicity which impedes their use to inhibit P-gp:
1- Cyclosporine: (hepatic, renal, myeloid and
neurotoxicity)
2- Verapamil: (cardiotoxicity)
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B) Second-generation agents :
These agents were selective and less toxic than the first
generation agents. Many chemotherapeutic agents are
substrate of P-gp and CYP 3A4. Same way, second
generation agents were also substrate of the CYP 3A4.
So these may lead to unpredictable absorption and
metabolism and these ultimately resulted into modified
bioavaibility:
1-Valspodar (R-enantiomer of Verapamil )
2-Biricodar
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C) Third-generation agents
These agents were not the substrates of CYP 3A4
so used to overcome drawback of second generation
agents and these agents
selectively and potentially inhibit P-gp.
1-Tariquidar XR9576
2- Zosuquidar LY335979
3- Laniquidar R101933
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II- Natural and Synthetic Polymers:
A- Natural polymers:
They are obtained from natural source. For example:
1-Anionic gums:
Xanthan gum P-gp inhibitor at 0.05%
Gellan gum :P-gp inhibitors at 0.05%
Dextran Xanthan gum :P-gp inhibitor at 0.05%
2- From Green tea: Polyphenols
3- From Grapefruit Juice: Various Polysaccharides
like D-glucose and/or D-glucuronic acid
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B- Synthetic polymers
Synthetic polymers can be synthesized by monomer
polymerization or by natural polymers modifications
or by combination of natural substances with
synthetic substances. e.g.: Detergents based on
Polyethylene glycol, Dendrimers and Thiomers.
The mechanism to inhibit P-gp by these polymeric
surfactants is believed to be mediated by modifying
the function of cell membrane lipid.
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Thiomers:These polymers have been newly implemented in the pharmaceutical area.
Polymers having thiol group has shown to have superior penetration improving properties.
Recently, many researchers have suggested that thiomers is having P-gp pump inhibitory activity due to thiol group because thiomersform disulfide bond between cysteine group of P-gp and free thiol group of thiomers.
For example: α-Chitosan–thiobutylamidine(chito– TBA)
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III- Nanocarrier drug delivery system:
Liposomes:
Liposomes are vesicles made up of bilayer or
multilayers that contain phospholipids and
cholesterol enveloping hydrophilic aqueous region.
Both lipophilic and hydrophilic drugs can be
encapsulated within this nanocarrier and is available
for absorption at the intestinal membrane surface.
Neutral phospholipids are selectively effluxed out by
P-gp so there would be competition for P-gp when
neutral phospholipids administered with P-gp
substrates.
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CONCLUSION
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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, and other xenobiotics.
The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy).
Drug-transporting proteins operate in pharmacokinetic and pharmacodynamic pathways, including pathways involved in both therapeutic and adverse effects
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Membrane transporters play a critical role in the
development of resistance to anticancer drugs,
antiviral agents, and anticonvulsants.
Various approaches have been developed to
overcome the effect of membrane transporters
include reversal agents, polymers & liposomes
which could enhance the effect of substrate drugs of
membrane transporters
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THANK YOU
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