Transporters: Focus on OATP1B1 and Selected Renal Transporters

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Transporters Focus on OATP1B1 and Selected
Renal Transporters Kathy Giacomini University
of California, San Francisco
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Selected Membrane Transporters in Human Genome
ENT1 ENT2
MATE1-2
MRP1-4
CNT1 CNT2 CNT3
Organic Cations
Nucleosides
Hydrophobic Anions
Nucleosides
MDR1 MDR3 BSEP
OCTs OCTNs OATs
Organic Ions
Hydrophobic Cations
VMAT VAChT
Neurotransmitters
Fe
Organic Anions
DAT NET GAT1 SERT
Oligopeptides
NRAMP1 DMT1 IREG1
OATPs
PEPT1 PEPT2
ABC Family 50
SLC Family 300
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Transporters in the Liver
Blood
MRP1,3
BCRP
OCT1
MDR1,3
OAT2
Bile
MRP2
OATP 1B1, 1B3 2B1
BSEP
NTCP
Hepatocyte
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Is OATP1B1 Important for Drug-Drug Interactions?

• What is the evidence?
• In vitro evidence
• In vivo evidence

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Selected Substrates of OATPs
OATP1B1 benzylpenicillin, atorvastatin,cerivasta
tin, fluvastatin, pitavastatin, pravastatin,
rosuvastatin, methotrexate, nateglinide,
repaglinide, rifampin OATP1B3 digoxin,
fexofenadine, fluvastatin, pravastatin,methotrexa
te, paclitaxel, rifampin OATP2B1
benzylpenicillin, fexofenadine, fluvastatin,
pravastatin
OATP 1B1
OATP 1B3
OATP 2B1
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Is OATP1B1 Important for Drug-Drug Interactions?

• What is the evidence?
• In vitro evidence
• In vivo evidence

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In Vivo Evidence

• Genetic Studies
• Knockout/transgenic Mice
• Polymorphisms in Humans
• Chemical Inhibition Studies

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In Vivo Evidence

• Genetic Studies
• Knockout Mice Not applicable
• Polymorphisms in Humans
• Chemical Inhibition Studies Specific inhibitors
• not available

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Individuals with Polymorphisms of OATP1B1 Have
Higher Plasma Levels of Repaglinide
Homozygous 521CC
Homozygous 521TT
Niemi M. et al, Clin Pharmacol Ther 2005
77468-78
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Individuals with Polymorphisms of ABCB1 Have
Similar Plasma Levels of Repaglinide
Niemi M. et al, Clin Pharmacol Ther 2005
77468-78
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Individuals with Polymorphisms of CYP3A5 Have
Similar Plasma Levels of Repaglinide
Niemi M. et al, Clin Pharmacol Ther 2005
77468-78
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Individuals with Polymorphisms of OATP1B1 Have
Higher Plasma Levels of Fexofenadine
Homozygous 521CC
Homozygous 521TT
Niemi M. et al, British Journal of Clinical
Pharmacology 2005, 59 602-604
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Individuals with Polymorphisms of OATP1B1 Have
Higher Plasma Levels of Pravastatin
11187GA
11187GG
Niemi M. et al, Pharmacogenetics. 2004
Jul14(7)429-40.
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Individuals with Polymorphisms of OATP1B1 Have
Higher Plasma Levels of Pravastatin
521CC
521TC
521TT
Niemi M. et al, Pharmacogenetics. 2004
Jul14(7)429-40.
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Individuals with Polymorphisms of OATP1B1 Have
Higher Plasma Levels of Pravastatin
17 Heterozygotes
Niemi M. et al, Pharmacogenetics. 2004
Jul14(7)429-40.
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OATP1B1
Genetic Studies Compelling Evidence
that OATP1B1 Plays a Role in Drug
Disposition Chemical Inhibition Studies
Specific inhibitors not available
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Drug-Drug Interactions with Repaglinide
Itraconazole CYP3A4 inhibitor P-gp
inhibitor Gemfibrozil CYP2C8 and OATP1B1
inhibitor
Niemi M. et al, Diabetologia. 2003
Mar46(3)347-51.
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Increase in Plasma Levels of Repaglinide by
Trimethoprim, A CYP2C8 Inhibitor
trimethoprim
Trimethoprim CYP2C8 inhibitor
Niemi M. et al, Br J Clin Pharmacol. 2004
Apr57(4)441-7
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OATP1B1
Genetic Studies Compelling evidence
that OATP1B1 plays a role in drug
disposition Chemical Inhibition Studies
Inhibitor studies are suggestive, but not
definitive.
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Recommendations to Consider

• Perform in vitro studies in cells expressing
  OATP1B1- Assess if NME is substrate/inhibitor
• If in vitro data show evidence of interaction
• with OATP1B1
• Substrate Possibly perform clinical
  Interaction study with gemfibrozil or
  rifampicin as inhibitor of NME
• Inhibitor Possibly perform clinical
  Interaction study
• with NME as inhibitor of fexofenadine (no
  metabolism)
• or atorvastatin/pravastatin

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Selected Membrane Transporters in Human Genome
ENT1 ENT2
MATE1-2
MRP1-4
CNT1 CNT2 CNT3
Organic Cations
Nucleosides
Hydrophobic Anions
Nucleosides
MDR1 MDR3 BSEP
OCTs OATs
Organic Ions
Hydrophobic Cations
VMAT VAChT
Neurotransmitters
Fe
Organic Anions
DAT NET GAT1 SERT
Oligopeptides
NRAMP1 DMT1 IREG1
OATPs
PEPT1 PEPT2
ABC Family 50
SLC Family 300
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Renal Drug Transporters
Urine
Blood
Li M et al. Expert Opin Drug Metab Toxicol 2006
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Expression of Various Renal Transporters in Human
Kidney
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OCT2, OAT1 and OAT3 Important for Drug-Drug
Interactions?

• What is the evidence?
• In vitro evidence
• In vivo evidence

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Selected Substrates of OATs and OCTs
OAT1 acyclovir, adefovir, cidofovir,
methotrexate OAT3 estrone sulfate,
methotrexate, cimetidine, tetracycline OCT2
amantadine, memantine, cimetidine, metformin
OAT1
OAT3
OCT2
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In Vivo Evidence

• Genetic Studies
• Knockout/transgenic Mice Available
• Polymorphisms in Humans
• Chemical Inhibition Studies Selective
• but not specific inhibitors are available

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Knockout Mouse Models

• Oat1-/- Mice
• Decreased CLR of para-aminohippurate,
  furosemide, endogenous organic anions (Eraly
  et al. J Biol Chem 2006)
• Oat3-/- Mice
• Reduced uptake of para-aminohippurate,
  estrone sulfate in kidney slices and choroid
  plexus (Sweet et al. J Biol Chem 2002 Sykes
  et al. AJP Ren Physiol 2004)
• Oct1/2-/- Mice
• Complete loss of active secretion of
  tetraethylammonium (Jonker et al. Mol Cell Biol
  2003)

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Preliminary Data on Cefotaxime and
GeneticVariants of OAT3 Unpublished Data
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Preliminary Data on Gabapentin and
GeneticVariants of OCTN1 Unpublished Data
Cells
Clinical
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Preliminary Data on Gabapentin and
GeneticVariants of OCTN1 Unpublished Data
Cells
Clinical
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In Vivo Evidence

• Genetic Studies
• Knockout/transgenic Mice Available
• Polymorphisms in Humans
• Chemical Inhibition Studies Selective
• but not specific inhibitors are available

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Drug-Drug Interactions Related to Renal Drug
Transporters

• Organic Anion Transporters (OATs)
• Cefazolin/Probenecid (38 ? cefazolin CLR)
• (Spina et al. Ann Pharmacother 2003, Sakurai et
  al. Pharm Res 2004)
• Organic Cation Transporters (OCTs)
• Procainamide/Cimetidine (42 ? procainamide CLR)
• (Somogyi et al. Eur J Clin Pharmacol 1983)
• Metformin/Cimetidine (28 ? metformin CLR)
• (Somogyi et al. Br J Clin Pharmacol 1987)

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Other DDIs Potentially Resulting From Renal
Transporter Interactions

• Methotrexate/NSAIDs
• Furosemide/Probenecid
• Pindolol/Cimetidine
• Amiloride/Cimetidine
• Procainamide/Trimethoprim

Charge Specific Inhibitors
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Recommendations to Consider

• Perform in vitro studies in cells expressing
  OAT1, OAT3 or OCT2- Assess if NME is
  substrate/inhibitor
• If in vitro data show evidence of interaction
  with OCT2, OAT1 or OAT3
• Substrate of OCT2 Cimetidine inhibition
• Inhibitor of OCT2 Metformin
• Substrate of OATs Probenecid
• Inhibitor of OATs Cefazolin