PHASE 3: Transporterbased DDIs 101 - PowerPoint PPT Presentation


Title: PHASE 3: Transporterbased DDIs 101


1
PHASE 3 Transporter-based DDIs 101
  • Jessica Oesterheld, MD

2
What you need to know to figure out
transporter-based DDIs
  • Different knowledge set than for CYPs
  • Answer 3 questions
  • on which organ does the transporter based DDI
    occur BBB, intestine,liver, renal proximal cell
  • Is the transporter an ABC or SLC- know if
    effluxer or influxer
  • on what membrane does the transporter reside
  • intestinal pgp / CYP3A4 tag team- DDI multiplier

3
Transporters
  • Until 30 years ago thought only lipid soluble
    drugs diffuse across intestine
  • Actually non-lipid soluble drugs can be
    transported (both influxed and effuxed) across
    both the apical and the basolateral borders by
    membrane-embedded transporters-way drugs move
    across cells.

4
Focus on ABCB1(p-gp)
  • ABCB1(p-pg) exist in membranes of tumor cells
    BBB, testes, placenta,they block entry of
    compounds into these sanctuaries
  • In kidney, liver and small intestine,
    ABCB1(p-gp) efflux compounds into the collecting
    tubule, biliary system, gut lumen - ABCB1 always
    on apical side (brush border, luminal)
  • Transports wide variety of substrates especially
    neutral and hydrophobic cations or amphipathic
    (mostly non-polar with one end polar

5
Transporters- functions
  • play a part in resistance to cancer cells
  • genetic polymorphisms are responsible for
    diseases
  • In intestine, hepatocytes, renal proximal tubule
    cells, blood transfer drugs in and out of organs
    into blood and target cells to breast milk, and
    protect sanctuaries like the brain, testes,
    placenta
  • Can cause DDIs
  • Considered Phase 3 reactions

6
Transporters-2 superfamilies
  • ATP-binding cassette (ABC) transporters
  • http//nutrigene.4t.com/humanabc.htm
  • Solute-Linked Carrier (SLC) transporters
  • www.bioparadigms.org/slc/menu.asp

7
ABC and SLCs
  • The ABC transporters are in a single family with
    a shared structural element and ontologic
    history-effluxing or exporting of endogenous and
    exogenous products
  • The SLC transporter families are a diverse group
    whose families share no common structural
    elements, and they are all transporters of a wide
    array of exogenous and endogenous products- some
    bidirectonal- but most influxing, importing

8
Nomenclature- ABCs
  • Usual family, subfamily and isoform convention
    -an integer represents the family (e.g., 1, 2), a
    letter, the subfamily (e.g., A, B, C) and an
    integer, the isoform (e.g., 1,2). e.g., CYP2D6,
    UGT1A1
  • Members of the ABC family all have the same
    systemic ABC designation since they are all in a
    single family and the first integer is
    skipped---- eg ABCB1(p-gp) --commonly followed by
    alias or common name

9
Nomenclature SLCs
  • SLC superfamily are not in a single family, their
    designation, SLC, is followed by an integer
    (family), letter (subfamily) and integer
    (isoform). There is a single exception in the SLC
    nomenclature. The SLC subfamily 21 is designated
    as SLCO instead of SLC-e.g., SLCO1B1 (OATP1B1)

10
ABCs/SLCs
  • organ specific and present on a particular
    membrane either luninal or basolateral border
    (Bblood)
  • have overlapping substrates, inhibitors and
    inducers
  • can have genetic variations
  • cause transporter-based DDIs in intestine, BBB,
    liver and kidney

11
History of transporters
  • 30 years ago, Juliano and Ling noted after
    initial efficacy, many anti-CA drugs stopped
    being effective at the same time Multiple Drug
    Resistance (MDR)
  • The gene MDR1 on chromosome 7 encodes a
    glycoprotein named P (permeability) glycoprotein
    that actively pumps out compounds from cell
  • Multiple drugs are effected at same time since
    ALL are P-gp substrates
  • Approximately 50 of human cancers express
    P-glycoprotein at levels sufficient to confer MDR
  • Intensive search for p-gp inhibitors (lately
    fluoxetine used with CA drug for colon cancer)

12
ABCs
  • There are ABC 49 transporters divided into 7
    subfamilies
  • ABCA (12), ABCB (11), ABCC (13), ABCD (4),
    ABCE (1), ABCF (3), ABCG (6)
  • flip compounds across a cellular gradient
    flippases or bouncersor hydrophobic vacuum
    cleaners
  • Different transporters involved with exogenous
    and endogenous compounds---- bile, glucuronides,
    organic anions, lipids.
  • Use ATP hydrolysis as driving force

13
Human diseases associated with an ABC Transporter
  • Disease Transporter
  • Cystic fibrosis ABCC7 (CFTR)
  • Stargardt disease AMD ABCA4 (ABCR)
  • Tangier Disease and Familial HDL deficiency
    ABCA1 (ABC1)
  • Progressive familial intrahepatic cholestasis
    ABCB11 (SPGP), ABCB4 (MDR2)
  • Dubin-Johnson syndrome ABCC2 (MRP2)
  • Pseudoxanthoma elasticum ABCC6 (MRP6)
  • Persistent hypoglycemia of infancy ABCC8
    (SUR1), ABCC9 (SUR2)
  • Sideroblastic anemia and ataxia
    ABCB7 (ABC7)
  • Adrenoleukodystrophy ABCD1 (ALD)
  • Sitosterolemia ABCG5, ABCG8
  • Immune deficiency ABCB2 (Tap1), ABCB3
    (Tap2)

14
Sub families B,C,G

15
(No Transcript)
16
Decrease bioavailability

Villus tip of enterocyte
17

BILIARY EXCRETION INTO GUT
18
Tubular secretion

reabsorbtion
19
Other BBB ABC transportersABCC4(MRP4),
ABCC5(MRP5), ABCG2(BCRP)
20
BBB-Some drugs are ABCB1(p-gp)substrates
  • Drugs can be ABCB1(p-gp) substrates or not
  • Older antihistamines are not ABCB1(p-gp)
    substrates- therefore they enter the BBB, but
    non-sedating antihistamines are ABCB1(p-gp)
    substrates and are excluded from the CNS and have
    less CNS side effects

21
BBB-Some drugs are ABCB1(p-gp) inhibitors/inducers
  • New kind of drug-drug interaction
  • Usually anti-diarrheal drug loperamide (Imodium)
    is excluded by BBB from CNS because it is a
    ABCB1(p-gp) substrate. If add quinidine which is
    a ABCB1(p-gp) inhibitor at sufficient dosage,
    patient will get CNS side effect or respiratory
    depression (Sadeque and Wandel 2000)

22
Intestine/kidney-Other ABCB1(p-gp) DDIs
  • Long known that when quinidine given with
    digoxin, it increased digoxin concentrations
  • But only a small portion of digoxin is handled by
    P450 enzymes
  • digoxin is a ABCB1(p-gp) substrate
  • Quinidine inhibits ABCB1 in intestine and kidney
    leading to more digoxin retained

23
dig
quinidine
24
TUBULAR SECRETION
dig

ACTIVE REABSORBTION
quinidine
25
CYP3A and ABCB1(p-gp) in gut-Intestinal Tag Team
  • Many substrates of ABCB1(p-gp) are also CYP3A4
    substrates
  • ABCB1(p-gps) efflux compound to lumen, then
    compound is reabsorbed this shuttle leads to
    increased exposure of compounds to CYP3A4 and
    maximizes their activity
  • If inhibit ABCB1(p-gps) then decrease CYP3A4
    efficiency (inhibit CYP3A4)
  • If inhibit both CYP3A4 and ABCB1 (p-gps) mulitply
    the combined inhibition of the CYP

26
Intestinal Cells
drug
pgp
3A4
B
L
drug
o
LUMEN
pgp
3A4
0
D
drug
pgp
3A4
P-gps in front- with repeated shuttles of
absorption/efflux Since substrates can diffuse
back in
27
Double Inhibitors/Double Inducers
  • Not only are many drugs both ABCB1 (p-gp) and
    CYP3A4 substrates, but many drugs are both ABCB1
    and CYP3A4 inhibitors (e.g., gfj, erythromycin,
    cyclosporine)
  • Many drugs are both ABCB1 and CYP3A4 inducers
    (e.g., St Johns wort, rifampin)
  • Therefore the effects of DDIs on double
    substrates by double inhibitors or double
    inducers are substantially increased
  • Coordination of their activity by nuclear
    receptor coordination -.Pregnane X Receptor (PXR)
    Constitutive Androstane Receptor (CAR) and
    perhaps others

28
Very difficult to predict and tease out
ABCB1(p-gp)-based DDIs
  • At least 2 binding sites and 2 ATP-binding sites
    on 2 symmetric non-identical halves of P-gp
  • Sites work cooperatively
  • Competitive inhibition, non-competitive
    inhibition and collective stimulation
  • Must also tease out CYP3A4 effects and other
    transporters

29
Intestinal/hepatic ABCB1(p-gp) Activity (Lin and
Yamazaki 2003)
  • ABCB1(p-gp) functional activity is saturable,
    therefore only important when drug is active at
    low dose or poor solubility
  • Only certain drugs are affected, especially those
    with high permeability and poor solubility

30
ABCB1(p-gp) Variability
  • Controversial whether men have 2.4 fold higher
    levels of ABCB1(P-gp) than women
  • May not be fully developed until 8 years of age
  • Increased in pregnancy (Hebert et al 2008)
  • SNP at exon 26 3435TT associated with lower
    ABCB1(p-gp) activity in duodenum and 2-fold
    higher digoxin concentration (Hoffmeyer et al
    2000)- these findings not consistently replicated
    (Dragonas 2008), part of haplotype
  • Haplotypehaploid genotype group of alleles of
    linked genes
  • However association of this SNP with postural
    hypotension from NT (Roberts 2002)
  • Varies from 16 to 27 in subjects of African
    descent to 48 to 57 in whites and 41 to 66 in
    Asians

31
SLCs
  • Diverse group without a common structure
  • 364 members 46 families
  • Members of same families must have 20 amino
    acids in common
  • Dont use ATP, but couple to another solute
    transporter or use favorable gradients
  • Generally influxers
  • Split into those that handle anions or cations
  • Transporters that handle anions (weak
    acids)OATs, OATPs, also MRPs
  • Transporters that handle cations (weak bases)
    OCTs, OCTNs, MATEs, also ABCB1

32
SLC6A4SERT
Also SLC46 and 47
33
SLC families involved in drug transport
  • (1) Proton Oligopeptide Transporters (SLC15) 4
    members
  • (2) Organic Anion Transporting Polpeptides
    (SLC21 known as SLCO) 20 members
  • (3) Organic Cation, Anion, and Zwitterions
    Transporters (SLC22) 18 members
  • (4) Multidrug and Toxin Extrusion Transporters
    (SLC47) 3 members

34
SLCO1A2 (OATP1A2)
  • Fexofenadine (Allegra) is a substrate
  • Grapefruit juice (naringin) inhibits this
    transporter and prevents entry to the intestinal
    cell and enters lumen instead-gt lower systemic
    levels of fexofenadine
  • Other juices- apple and orange do the same thing
    (Bailey et al 2007)

35
fexofexadine
gfj
36
SLC22A6 (OAT1)- organic anion transporters
  • Cidofovir (Vistide) used for CMD retinitis- in
    order to prevent renal toxicity if it accumulates
    in kidney, given with probenecid and blocks
    entrance to kidney
  • Probenecid originally developed to increase
    systemic levels of penicillin during WW2 when
    penicillin was scarce

37
Cidofovir
oct2
Probenecid
38
Liver
  • SLC transporters on the basolateral or portal
    side of liver- influxes the substrate into the
    liver
  • If transporter is inhibited, leads to increased
    levels of the substrate
  • ABC transporters embedded in the opposite
    membrane effluxes the substrate into the biliary
    caniculi

39
SLCO1B1 (OAT1B1)
  • Substrates which can be influxed into liver
    include irinotecan, penicillin G, most statins,
    methotrexate, repaglinide, rifampin
  • Inhibitors of SLCO1B1 include cyclosporine,
    gemfibrozil, clarithromycin, indinavir,ritonavir,
    saquinavir and surprisingly rifampin

40

41
pravastatin
  • Influxed into liver via SLCO1B1 (OATP1B1) and
    effluxed into billiary caniculi via ABCC2
    (MRP2)----- with other minor transporter pathways
  • Phase 1 and 2 enzymes in liver, but their effects
    minimal.
  • Gemfibrozil inhibits SLCO1B1 and increases AUC
    more than 200 (Pravachol website-combination
    therapy not recommended)

42
Pravastatin and Gemfibrozil DDI
  • This DDI is a risk factor for the development of
    rhabdomyolitis
  • Independent of risk factor from additive risk
    factor from both drugs individually
  • In this case there is not separate effect via
    CYPs

43
Transporter CYP DDIs
  • Gemfibrozil is not only a SLCO1B1 inhibitor, but
    it is also a CYP2C8 inhibitor
  • Plasma concentration of replaginide (Prandin) is
    increased 20 fold because it is both a SLCO1B1
    substrate and CYP2C8 substrate (Niemi et al.
    2003)

44
replaginide

Genetic variations of SLCO1B1- decreased
transporter activity also leads to increased AUC
of substrate
gemfibrozil
45
Genetics of SLCO1B1 haplotypes
  • SLCO1B115 is present in 15 of
    European-Americans associated with higher
    pravastatin levels and several other SLCO1B1
    (OATP1B1) substrates
  • Also associated with increased risk of
    simvastatin-induced myopathy
  • SLCO1B11B associated with reduced plasma
    concentrations of some SLCO1B1 substrates
  • Haplotypehaploid genotype group of alleles of
    linked genes

46
Status of transporter-based DDIs
  • Nomenclature of SLCs standardized with new SLCs
    added in last 2 years
  • Few selective substrate or inhibitors
  • In vitro DDIs may not translate into in vivo ones
  • In vivo, knock-out mice may not translate to
    humans-recent development of humanized
    transgenetic mice or humanized by transplanting
    hepatocytes
  • In vivo human studies need to tease out effect
    from CYPs, UGTs and other transporters
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Title: PHASE 3: Transporterbased DDIs 101


1
PHASE 3 Transporter-based DDIs 101
  • Jessica Oesterheld, MD

2
What you need to know to figure out
transporter-based DDIs
  • Different knowledge set than for CYPs
  • Answer 3 questions
  • on which organ does the transporter based DDI
    occur BBB, intestine,liver, renal proximal cell
  • Is the transporter an ABC or SLC- know if
    effluxer or influxer
  • on what membrane does the transporter reside
  • intestinal pgp / CYP3A4 tag team- DDI multiplier

3
Transporters
  • Until 30 years ago thought only lipid soluble
    drugs diffuse across intestine
  • Actually non-lipid soluble drugs can be
    transported (both influxed and effuxed) across
    both the apical and the basolateral borders by
    membrane-embedded transporters-way drugs move
    across cells.

4
Focus on ABCB1(p-gp)
  • ABCB1(p-pg) exist in membranes of tumor cells
    BBB, testes, placenta,they block entry of
    compounds into these sanctuaries
  • In kidney, liver and small intestine,
    ABCB1(p-gp) efflux compounds into the collecting
    tubule, biliary system, gut lumen - ABCB1 always
    on apical side (brush border, luminal)
  • Transports wide variety of substrates especially
    neutral and hydrophobic cations or amphipathic
    (mostly non-polar with one end polar

5
Transporters- functions
  • play a part in resistance to cancer cells
  • genetic polymorphisms are responsible for
    diseases
  • In intestine, hepatocytes, renal proximal tubule
    cells, blood transfer drugs in and out of organs
    into blood and target cells to breast milk, and
    protect sanctuaries like the brain, testes,
    placenta
  • Can cause DDIs
  • Considered Phase 3 reactions

6
Transporters-2 superfamilies
  • ATP-binding cassette (ABC) transporters
  • http//nutrigene.4t.com/humanabc.htm
  • Solute-Linked Carrier (SLC) transporters
  • www.bioparadigms.org/slc/menu.asp

7
ABC and SLCs
  • The ABC transporters are in a single family with
    a shared structural element and ontologic
    history-effluxing or exporting of endogenous and
    exogenous products
  • The SLC transporter families are a diverse group
    whose families share no common structural
    elements, and they are all transporters of a wide
    array of exogenous and endogenous products- some
    bidirectonal- but most influxing, importing

8
Nomenclature- ABCs
  • Usual family, subfamily and isoform convention
    -an integer represents the family (e.g., 1, 2), a
    letter, the subfamily (e.g., A, B, C) and an
    integer, the isoform (e.g., 1,2). e.g., CYP2D6,
    UGT1A1
  • Members of the ABC family all have the same
    systemic ABC designation since they are all in a
    single family and the first integer is
    skipped---- eg ABCB1(p-gp) --commonly followed by
    alias or common name

9
Nomenclature SLCs
  • SLC superfamily are not in a single family, their
    designation, SLC, is followed by an integer
    (family), letter (subfamily) and integer
    (isoform). There is a single exception in the SLC
    nomenclature. The SLC subfamily 21 is designated
    as SLCO instead of SLC-e.g., SLCO1B1 (OATP1B1)

10
ABCs/SLCs
  • organ specific and present on a particular
    membrane either luninal or basolateral border
    (Bblood)
  • have overlapping substrates, inhibitors and
    inducers
  • can have genetic variations
  • cause transporter-based DDIs in intestine, BBB,
    liver and kidney

11
History of transporters
  • 30 years ago, Juliano and Ling noted after
    initial efficacy, many anti-CA drugs stopped
    being effective at the same time Multiple Drug
    Resistance (MDR)
  • The gene MDR1 on chromosome 7 encodes a
    glycoprotein named P (permeability) glycoprotein
    that actively pumps out compounds from cell
  • Multiple drugs are effected at same time since
    ALL are P-gp substrates
  • Approximately 50 of human cancers express
    P-glycoprotein at levels sufficient to confer MDR
  • Intensive search for p-gp inhibitors (lately
    fluoxetine used with CA drug for colon cancer)

12
ABCs
  • There are ABC 49 transporters divided into 7
    subfamilies
  • ABCA (12), ABCB (11), ABCC (13), ABCD (4),
    ABCE (1), ABCF (3), ABCG (6)
  • flip compounds across a cellular gradient
    flippases or bouncersor hydrophobic vacuum
    cleaners
  • Different transporters involved with exogenous
    and endogenous compounds---- bile, glucuronides,
    organic anions, lipids.
  • Use ATP hydrolysis as driving force

13
Human diseases associated with an ABC Transporter
  • Disease Transporter
  • Cystic fibrosis ABCC7 (CFTR)
  • Stargardt disease AMD ABCA4 (ABCR)
  • Tangier Disease and Familial HDL deficiency
    ABCA1 (ABC1)
  • Progressive familial intrahepatic cholestasis
    ABCB11 (SPGP), ABCB4 (MDR2)
  • Dubin-Johnson syndrome ABCC2 (MRP2)
  • Pseudoxanthoma elasticum ABCC6 (MRP6)
  • Persistent hypoglycemia of infancy ABCC8
    (SUR1), ABCC9 (SUR2)
  • Sideroblastic anemia and ataxia
    ABCB7 (ABC7)
  • Adrenoleukodystrophy ABCD1 (ALD)
  • Sitosterolemia ABCG5, ABCG8
  • Immune deficiency ABCB2 (Tap1), ABCB3
    (Tap2)

14
Sub families B,C,G

15
(No Transcript)
16
Decrease bioavailability

Villus tip of enterocyte
17

BILIARY EXCRETION INTO GUT
18
Tubular secretion

reabsorbtion
19
Other BBB ABC transportersABCC4(MRP4),
ABCC5(MRP5), ABCG2(BCRP)
20
BBB-Some drugs are ABCB1(p-gp)substrates
  • Drugs can be ABCB1(p-gp) substrates or not
  • Older antihistamines are not ABCB1(p-gp)
    substrates- therefore they enter the BBB, but
    non-sedating antihistamines are ABCB1(p-gp)
    substrates and are excluded from the CNS and have
    less CNS side effects

21
BBB-Some drugs are ABCB1(p-gp) inhibitors/inducers
  • New kind of drug-drug interaction
  • Usually anti-diarrheal drug loperamide (Imodium)
    is excluded by BBB from CNS because it is a
    ABCB1(p-gp) substrate. If add quinidine which is
    a ABCB1(p-gp) inhibitor at sufficient dosage,
    patient will get CNS side effect or respiratory
    depression (Sadeque and Wandel 2000)

22
Intestine/kidney-Other ABCB1(p-gp) DDIs
  • Long known that when quinidine given with
    digoxin, it increased digoxin concentrations
  • But only a small portion of digoxin is handled by
    P450 enzymes
  • digoxin is a ABCB1(p-gp) substrate
  • Quinidine inhibits ABCB1 in intestine and kidney
    leading to more digoxin retained

23
dig
quinidine
24
TUBULAR SECRETION
dig

ACTIVE REABSORBTION
quinidine
25
CYP3A and ABCB1(p-gp) in gut-Intestinal Tag Team
  • Many substrates of ABCB1(p-gp) are also CYP3A4
    substrates
  • ABCB1(p-gps) efflux compound to lumen, then
    compound is reabsorbed this shuttle leads to
    increased exposure of compounds to CYP3A4 and
    maximizes their activity
  • If inhibit ABCB1(p-gps) then decrease CYP3A4
    efficiency (inhibit CYP3A4)
  • If inhibit both CYP3A4 and ABCB1 (p-gps) mulitply
    the combined inhibition of the CYP

26
Intestinal Cells
drug
pgp
3A4
B
L
drug
o
LUMEN
pgp
3A4
0
D
drug
pgp
3A4
P-gps in front- with repeated shuttles of
absorption/efflux Since substrates can diffuse
back in
27
Double Inhibitors/Double Inducers
  • Not only are many drugs both ABCB1 (p-gp) and
    CYP3A4 substrates, but many drugs are both ABCB1
    and CYP3A4 inhibitors (e.g., gfj, erythromycin,
    cyclosporine)
  • Many drugs are both ABCB1 and CYP3A4 inducers
    (e.g., St Johns wort, rifampin)
  • Therefore the effects of DDIs on double
    substrates by double inhibitors or double
    inducers are substantially increased
  • Coordination of their activity by nuclear
    receptor coordination -.Pregnane X Receptor (PXR)
    Constitutive Androstane Receptor (CAR) and
    perhaps others

28
Very difficult to predict and tease out
ABCB1(p-gp)-based DDIs
  • At least 2 binding sites and 2 ATP-binding sites
    on 2 symmetric non-identical halves of P-gp
  • Sites work cooperatively
  • Competitive inhibition, non-competitive
    inhibition and collective stimulation
  • Must also tease out CYP3A4 effects and other
    transporters

29
Intestinal/hepatic ABCB1(p-gp) Activity (Lin and
Yamazaki 2003)
  • ABCB1(p-gp) functional activity is saturable,
    therefore only important when drug is active at
    low dose or poor solubility
  • Only certain drugs are affected, especially those
    with high permeability and poor solubility

30
ABCB1(p-gp) Variability
  • Controversial whether men have 2.4 fold higher
    levels of ABCB1(P-gp) than women
  • May not be fully developed until 8 years of age
  • Increased in pregnancy (Hebert et al 2008)
  • SNP at exon 26 3435TT associated with lower
    ABCB1(p-gp) activity in duodenum and 2-fold
    higher digoxin concentration (Hoffmeyer et al
    2000)- these findings not consistently replicated
    (Dragonas 2008), part of haplotype
  • Haplotypehaploid genotype group of alleles of
    linked genes
  • However association of this SNP with postural
    hypotension from NT (Roberts 2002)
  • Varies from 16 to 27 in subjects of African
    descent to 48 to 57 in whites and 41 to 66 in
    Asians

31
SLCs
  • Diverse group without a common structure
  • 364 members 46 families
  • Members of same families must have 20 amino
    acids in common
  • Dont use ATP, but couple to another solute
    transporter or use favorable gradients
  • Generally influxers
  • Split into those that handle anions or cations
  • Transporters that handle anions (weak
    acids)OATs, OATPs, also MRPs
  • Transporters that handle cations (weak bases)
    OCTs, OCTNs, MATEs, also ABCB1

32
SLC6A4SERT
Also SLC46 and 47
33
SLC families involved in drug transport
  • (1) Proton Oligopeptide Transporters (SLC15) 4
    members
  • (2) Organic Anion Transporting Polpeptides
    (SLC21 known as SLCO) 20 members
  • (3) Organic Cation, Anion, and Zwitterions
    Transporters (SLC22) 18 members
  • (4) Multidrug and Toxin Extrusion Transporters
    (SLC47) 3 members

34
SLCO1A2 (OATP1A2)
  • Fexofenadine (Allegra) is a substrate
  • Grapefruit juice (naringin) inhibits this
    transporter and prevents entry to the intestinal
    cell and enters lumen instead-gt lower systemic
    levels of fexofenadine
  • Other juices- apple and orange do the same thing
    (Bailey et al 2007)

35
fexofexadine
gfj
36
SLC22A6 (OAT1)- organic anion transporters
  • Cidofovir (Vistide) used for CMD retinitis- in
    order to prevent renal toxicity if it accumulates
    in kidney, given with probenecid and blocks
    entrance to kidney
  • Probenecid originally developed to increase
    systemic levels of penicillin during WW2 when
    penicillin was scarce

37
Cidofovir
oct2
Probenecid
38
Liver
  • SLC transporters on the basolateral or portal
    side of liver- influxes the substrate into the
    liver
  • If transporter is inhibited, leads to increased
    levels of the substrate
  • ABC transporters embedded in the opposite
    membrane effluxes the substrate into the biliary
    caniculi

39
SLCO1B1 (OAT1B1)
  • Substrates which can be influxed into liver
    include irinotecan, penicillin G, most statins,
    methotrexate, repaglinide, rifampin
  • Inhibitors of SLCO1B1 include cyclosporine,
    gemfibrozil, clarithromycin, indinavir,ritonavir,
    saquinavir and surprisingly rifampin

40

41
pravastatin
  • Influxed into liver via SLCO1B1 (OATP1B1) and
    effluxed into billiary caniculi via ABCC2
    (MRP2)----- with other minor transporter pathways
  • Phase 1 and 2 enzymes in liver, but their effects
    minimal.
  • Gemfibrozil inhibits SLCO1B1 and increases AUC
    more than 200 (Pravachol website-combination
    therapy not recommended)

42
Pravastatin and Gemfibrozil DDI
  • This DDI is a risk factor for the development of
    rhabdomyolitis
  • Independent of risk factor from additive risk
    factor from both drugs individually
  • In this case there is not separate effect via
    CYPs

43
Transporter CYP DDIs
  • Gemfibrozil is not only a SLCO1B1 inhibitor, but
    it is also a CYP2C8 inhibitor
  • Plasma concentration of replaginide (Prandin) is
    increased 20 fold because it is both a SLCO1B1
    substrate and CYP2C8 substrate (Niemi et al.
    2003)

44
replaginide

Genetic variations of SLCO1B1- decreased
transporter activity also leads to increased AUC
of substrate
gemfibrozil
45
Genetics of SLCO1B1 haplotypes
  • SLCO1B115 is present in 15 of
    European-Americans associated with higher
    pravastatin levels and several other SLCO1B1
    (OATP1B1) substrates
  • Also associated with increased risk of
    simvastatin-induced myopathy
  • SLCO1B11B associated with reduced plasma
    concentrations of some SLCO1B1 substrates
  • Haplotypehaploid genotype group of alleles of
    linked genes

46
Status of transporter-based DDIs
  • Nomenclature of SLCs standardized with new SLCs
    added in last 2 years
  • Few selective substrate or inhibitors
  • In vitro DDIs may not translate into in vivo ones
  • In vivo, knock-out mice may not translate to
    humans-recent development of humanized
    transgenetic mice or humanized by transplanting
    hepatocytes
  • In vivo human studies need to tease out effect
    from CYPs, UGTs and other transporters
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