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Transporters: Focus on OATP1B1 and Selected Renal Transporters Kathy Giacomini University of California, San Francisco

Transporters: Focus on OATP1B1 and Selected Renal Transporters Kathy Giacomini University of California, San Francisco. Selected Membrane Transporters in Human Genome. ENT1 ENT2. MATE1-2. MRP1-4. CNT1 CNT2 CNT3. Organic Cations. Nucleosides. Hydrophobic Anions. Nucleosides. MDR1

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Transporters: Focus on OATP1B1 and Selected Renal Transporters Kathy Giacomini University of California, San Francisco

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  1. Transporters: Focus on OATP1B1 and Selected Renal Transporters Kathy Giacomini University of California, San Francisco

  2. 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

  3. Transporters in the Liver Blood MRP1,3 BCRP OCT1 MDR1,3 OAT2 Bile MRP2 OATP 1B1, 1B3 2B1 BSEP NTCP Hepatocyte

  4. Is OATP1B1 Important for Drug-Drug Interactions? • What is the evidence? • In vitro evidence • In vivo evidence

  5. Selected Substrates of OATPs OATP1B1:benzylpenicillin, atorvastatin,cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin OATP1B3:digoxin, fexofenadine, fluvastatin, pravastatin,methotrexate, paclitaxel, rifampin OATP2B1:benzylpenicillin, fexofenadine, fluvastatin, pravastatin OATP 1B1 OATP 1B3 OATP 2B1

  6. Is OATP1B1 Important for Drug-Drug Interactions? • What is the evidence? • In vitro evidence • In vivo evidence

  7. In Vivo Evidence • Genetic Studies • Knockout/transgenic Mice • Polymorphisms in Humans • Chemical Inhibition Studies

  8. In Vivo Evidence • Genetic Studies • Knockout Mice: Not applicable • Polymorphisms in Humans • Chemical Inhibition Studies:Specific inhibitors • not available

  9. Individuals with Polymorphisms of OATP1B1 Have Higher Plasma Levels of Repaglinide Homozygous 521CC Homozygous 521TT Niemi M. et al, Clin Pharmacol Ther 2005; 77:468-78

  10. Individuals with Polymorphisms of ABCB1 Have Similar Plasma Levels of Repaglinide Niemi M. et al, Clin Pharmacol Ther 2005; 77:468-78

  11. Individuals with Polymorphisms of CYP3A5 Have Similar Plasma Levels of Repaglinide Niemi M. et al, Clin Pharmacol Ther 2005; 77:468-78

  12. 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

  13. Individuals with Polymorphisms of OATP1B1 Have Higher Plasma Levels of Pravastatin 11187GA 11187GG Niemi M. et al, Pharmacogenetics. 2004 Jul;14(7):429-40.

  14. Individuals with Polymorphisms of OATP1B1 Have Higher Plasma Levels of Pravastatin 521CC 521TC 521TT Niemi M. et al, Pharmacogenetics. 2004 Jul;14(7):429-40.

  15. Individuals with Polymorphisms of OATP1B1 Have Higher Plasma Levels of Pravastatin *17 Heterozygotes Niemi M. et al, Pharmacogenetics. 2004 Jul;14(7):429-40.

  16. OATP1B1 Genetic Studies:Compelling Evidence that OATP1B1 Plays a Role in Drug Disposition Chemical Inhibition Studies:Specific inhibitors not available

  17. +itraconazole+gemfibrozil +gemfibrozil +itraconazole Drug-Drug Interactions with Repaglinide Itraconazole: CYP3A4 inhibitor P-gp inhibitor Gemfibrozil: CYP2C8 and OATP1B1 inhibitor Niemi M. et al, Diabetologia. 2003 Mar;46(3):347-51.

  18. Increase in Plasma Levels of Repaglinide by Trimethoprim, A CYP2C8 Inhibitor +trimethoprim Trimethoprim: CYP2C8 inhibitor Niemi M. et al, Br J Clin Pharmacol. 2004 Apr;57(4):441-7

  19. OATP1B1 Genetic Studies:Compelling evidence that OATP1B1 plays a role in drug disposition Chemical Inhibition Studies:Inhibitor studies are suggestive, but not definitive.

  20. 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

  21. 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

  22. MATE -1 OCTN1/2 hOCT2/3 hOAT1/3 Renal Drug Transporters Urine Blood Li M et al. Expert Opin Drug Metab Toxicol 2006

  23. Organic Cation Transporters (OCTs/OCTNs) OCT2 Organic Anion Transporters (OATs) OAT1 OAT3 Expression of Various Renal Transporters in Human Kidney

  24. OCT2, OAT1 and OAT3: Important for Drug-Drug Interactions? • What is the evidence? • In vitro evidence • In vivo evidence

  25. OCTN1 OCTN2 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

  26. In Vivo Evidence • Genetic Studies • Knockout/transgenic Mice: Available • Polymorphisms in Humans • Chemical Inhibition Studies: Selective • but not specific inhibitors are available

  27. 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)

  28. p = 0.045 Preliminary Data on Cefotaxime and GeneticVariants of OAT3: Unpublished Data

  29. p = 0.045 Preliminary Data on Gabapentin and GeneticVariants of OCTN1: Unpublished Data Cells Clinical

  30. p = 0.007 Preliminary Data on Gabapentin and GeneticVariants of OCTN1: Unpublished Data Cells Clinical

  31. In Vivo Evidence • Genetic Studies • Knockout/transgenic Mice: Available • Polymorphisms in Humans • Chemical Inhibition Studies: Selective • but not specific inhibitors are available

  32. 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)

  33. Other DDIs Potentially Resulting From Renal Transporter Interactions • Methotrexate/NSAIDs • Furosemide/Probenecid • Pindolol/Cimetidine • Amiloride/Cimetidine • Procainamide/Trimethoprim Charge Specific Inhibitors

  34. 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

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