1. Intestinal
Transporters in drug
absorption
Omer mustapha
Lab of physical and
industrial pharmacy
MS leading to phd
Hanyang university erica
korea
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2. Contents
1. Organic Anion Transporters (OAT)
2. Organic Cation Transporters (OCT)
3. Nucleoside Transporters
4. Monocarboxylate Transporters
5. Impact of intestinal transporters on
bioavailability
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3. 1. Organic Anion Transporters
(OAT, SLCO, OATP)
• Ionic agents generally exhibit low passive membrane
permeability, resulting in their poor bioavailability.
• An organic anion-transporter is a membrane
transport protein or 'transporter' that transports
organic anions across the cell membrane.
• These are present in the lipid bilayer of the cell
membrane. OATs belong to the Solute Carrier
Family (SLC), more specifically the Solute Carrier
Organic Anion (SLCO) gene subfamily.
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4. • Organic anion transporters are classified into
1. Organic anion transporters (OATs)
2. Organic anion transporting polypeptides
(OATPs)
3. Multiple drug resistance-associated
proteins(MRPs)
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5. Organic anion transporters (OAT)
• Five structurally related isoforms i.e. OAT 1-
OAT 5 have been identified.
• These are expressed in the kidney and have
important functions in renal clearance.
• OAT2 is expressed at higher levels in liver as
compared to kidney.
• OATs are also expressed to a lesser extent in
brain, muscle, eye and placenta.
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7. • Topology characteristics include twelve 12
α-helix two transmembrane domains
(TMD), one large hydrophilic extracellular loop
between TMD 1 and TMD 2 carrying
glycosylation sites and a large intracellular
loop containing multiple phosphorylation sites
between TMD 6 and TMD 7.
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8. • OATs are polyspecific transporters that interact
with various clinically significant organic anion
drugs such as
• Non steroidal anti-inflammatory drugs
(NSAIDs), β-lactam antibiotics, antiviral
drugs, diuretics, antitumor drugs and
angiotensin-converting enzyme inhibitors .
• The role of OAT family in the intestinal absorption
of drugs seems negligible because they have not
been identified in human intestine.
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9. Organic anion transporting polypeptides
(OATPs)
• OATPs are the rapidly expanding family of
mammalian transporters and transport a wide
range of amphipathic endogenous and
exogenous organic compounds.
• The topology include twelve TMD containing a
large extracellular domain with multiple
glycosylation sites.
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10. • OATP mediate transmembrane transport of wide range of
organic compounds
1. organic anions, such as bromosulfophthalein (BSP), bile
salts, bilirubin, prostaglandins, and estrogen-conjugates;
2. neural steroids and steroid conjugates;
3. lipophilic organic cations, e.g., rocuronium; and
4. organic dyes, thyroid hormones, and anionic
oligopeptides.
• Various pharmaceutically relevant compounds such as
digoxin, pravastatin, methotrexate, temocaprilat, benzylpen
icillin, fexofenadine,(D-Pen2, D-Pen5)-enkephalin
(DPDPE), as well as some NSAIDs.
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11. • Mechanism driving OATP mediated transport
are
1. Na+-independent manner
2. Anion exchange mechanism
3. Glutathione substrate transport
4. Proton-coupled transport mechanism
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12. • Expression of OATPs (OATP-C and OATP-8 occur at
the basolateral membrane of hepatocytes
• While other OATPs like OATP-B, OATP-D and
OATP-E are fairly expressed in tissues including
blood-brain barrier, lung, heart, kidney, placenta
and intestine.
• The regulation of OATPs expression and
functional kinetics can occur at both
transcriptional and post-transcriptional levels.
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13. 2. Organic Cation Transporters
(OCT, OCTN)
• An organic Cation transport protein mediates
the transport of organic cations, zwitterions
and anions across the cell membrane. These
proteins are members of the solute carrier
family, subfamily 22.
• Topology characteristics are similar as OATs.
• They have two distinct subfamilies i.e. OCT
and OCTN both of them having multiple
species.
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14. • OCT1-3, are polyspecific transporters capable of
transporting wide range of organic cations like
tetraethylammonium (TEA) and N-methylquinine, 1-
methyl-4-phenylpyridium (MPP+), antiviral, metformin
monoamine neurotransmitters
acetylcholine, dopamine, serotonin, histamine, choline etc.
• Physiological compounds such as creatinine, guanidine, and
thiamine.
• Pharmaceuticals like desipramine, an antidepressant
cimetidine, acyclovir, ganicyclovir and α Blocker Prazosin.
• Members of the OCTN subfamily have differential abilities
to interact with a variety of organic cation drugs, as well as
carnitine.
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15. • OCTs translocate organic cations and
compounds in an electrogenic manner (i.e.
producing a change in the electrical potential
of a cell).
• Na+ ions and H+ independent.
• Driving force is provided by substrate
concentration gradient and the membrane
potential.
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• OCTs isoforms are mainly
expressed in liver or kidney.
• To a lesser extent in
heart, skeletal
muscles, placenta, prostrate
and small intestine.
• OSTNs were also detected in
intetestinal enterocytes.

17. • The regulation of OCTs is associated with
phosphorylation / dephosphorylation of the
transporters.
• A gender dependent difference was also
observed in a study in rats.
• Another study showed OCTs level gradually
increase from infants to adults.
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18. Nucleoside Transporters (CNT, ENT)
• Nucleosides are the ribosylated precursors of purine
and pyrimidine nucleotides, these not only help in
cellular energy and signal transduction in the form of
their phosphorylated analogs (e.g., ATP and
cAMP, respectively), but also have other physiological
functions.
• E.g. cardiac and vascular effects, adenosine act as a
neuromodulator, inhibit lipolysis in fat cells and act
as an anti-inflammatory.
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19. • The cellular transport of nucleosides is
mediated by two distinct families the high
affinity, concentrative nucleoside transporters
(CNT; SLC28) and the low affinity, equilibrative
nucleoside transporters (ENT; SLC29).
• These transporter have distinguished
structural features and transport mechanisms.
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20. Concentrative Nucleoside Transporter
(CNT)
• CNT consists of three subtypes CNT1-CNT3.
• These are comprised of 13 putative TMD and
exhibits several protein kinase C phosphorylation
sites.
• They have wide range of substrate specificities
e.g. pyrimidine nucleotides, purine
adenosine, uridine and purine nucleotides.
• Pharmaceutical compounds include nucleoside
analogs e.g zidovudine, lamivudine, cytidine
cladrabine etc.
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21. • CNT expression has been shown in small
intestine, kideny, liver, heart, brain, placenta, p
ancreas, skeletal muscle, colon, rectum
mammary gland, bone marrow, trachea
prostrate and testis.
• CNT family is sodium dependent and works
through an active symport mechanism.
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22. Equilibrative Nucleoside Transporters
(ENT; SLC29)
• ENT consist of four subtypes ENT1- ENT4.
• They are characterized by 11 putative TMD
with an intracellular amine terminus and
extracellular carboxy terminus and exhibit
glycosylation sites in extracellular loops.
• ENT transport is mediated via a bidirectional
facilitated diffusion mechanism which is
dependent upon substrate concentration
gradient.
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23. • The substrate specificities are for endogenous
nucleosides and therapeutic nucleoside analogs.
• Phamaceuticalcompounds like
cladribine, gemicitabine, fludarabine, cytarabine,
purine and pyrimidine analogs and transport
nucleobase adenine.
• These transporters are widely expressed on the
mRNA level. Distributed between the apical and
basolateral membranes to mediate flux of
nucloesides.
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24. Monocarboxylate Transporters
(MCT)
• MCTs, constitute a family of proton-
linked plasma membrane transporters that
carry molecules having one carboxylate group
(monocarboxylates).
• 14 members of this family are identified each
having unique tissue distribution.
• MCT isoforms exhibit 12 putative TMD, with
both the amine and carboxy termini located
intracellularly.
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25. • MCTs have a high affinity for many
endogenous and exogenous short chain
anionic compounds e.g. lactic acid, pyruvate,
acetoacetate, β-hydroxybutyrate, acetate,
propionate and butyrate.
• MCT isoforms mainly expressed in
gastrointestinal tract. Localized apically or
basolaterally.
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26. 4. Impact of Intestinal Transporters on
Bioavailability
• The interplay of various transporter protein
mechanisms along with transport by parallel
pathways can significantly impact on the overall
bioavailability of a compound.
• Drug transporters play an important role in
intestinal drug absorption and secretion, and can
be major determinants of oral bioavailability.
• Transporters exhibit affinity for an extraordinary
range of compounds and provide great insight for
advancing the field of rational drug design.
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27. • By understanding the substrate
specificity, transport mechanism, and
expression profile of transporters, efficient
intestinal absorption may be made feasible by
strategies including appropriately modifying
either the structural recognition elements of
NCEs or through rational formulation design
to tailor optimized drug delivery.
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