Review
Clinical Importance of OATP1B1 and OATP1B3 in Drug­Drug Interactions

https://doi.org/10.2133/dmpk.DMPK-10-RV-094Get rights and content

Summary:

OATP1B1 and OATP1B3 are transporters that are expressed on the sinusoidal membrane of hepatocytes; they accept a number of therapeutic reagents as their substrates. In vitro and in vivo studies have shown that some drugs inhibit these transporters and cause clinically relevant drug­drug interactions (DDIs). Among these drugs, cyclosporin A markedly increases the plasma concentrations of OATP1B1 substrates. In such cases, the area under the plasma concentration­time curve and the maximum concentration of the affected drugs are increased to a similar degree. Even for OATP1B1 substrates that are metabolized in the liver, the hepatic uptake rate is a determinant of overall hepatic clearance, and the DDIs are partly caused by the inhibition of OATP1B1. Gemfibrozil displays DDIs with some OATP1B1 substrates, although their extent is small. Rifampicin and some HIV protease inhibitors are also OATP1B1 inhibitors. Rifampicin is also an inducer of metabolic enzymes, and although its single coadministration produces an increase in the plasma concentration of the affected drugs, multiple coadministrations may result in reductions in the plasma concentrations of OATP1B1 and CYP3A4 bisubstrates. As a large number of therapeutic reagents are substrates and/or inhibitors of OATP1B1 and OATP1B3, we should be aware of DDIs caused by the inhibition of these transporters.

References (93)

  • A. Asberg et al.

    Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients

    Am. J. Transplant.

    (2001)
  • I. Binet et al.

    Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A

    Kidney Int.

    (2000)
  • K. Ito et al.

    Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver

    Pharmacol. Rev.

    (1998)
  • Y. Ohno et al.

    General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs

    Clin. Pharmacokinet.

    (2007)
  • Y. Ohno et al.

    General framework for the prediction of oral drug interactions caused by CYP3A4 induction from in vivo information

    Clin. Pharmacokinet.

    (2008)
  • J. Houston et al.

    In vitro techniques to study drug-drug interactions of drug metabolism: Cytochrome P450

  • A. Grover et al.

    Transporter-based drug-drug interactions and their effect on distribution volumes

  • Y. Tanigawara

    Role of P-glycoprotein in drug disposition

    Ther. Drug Monit.

    (2000)
  • L.Z. Benet et al.

    Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data

    Curr. Drug Metab.

    (2003)
  • U. Hoffmann et al.

    The ABC transporters MDR1 and MRP2: multiple functions in disposition of xenobiotics and drug resistance

    Drug Metab. Rev.

    (2004)
  • A. Aszalos

    P-glycoprotein-based drug-drug interactions: preclinical methods and relevance to clinical observations

    Arch. Pharm. Res.

    (2004)
  • S. Zhou et al.

    Herbal modulation of P-glycoprotein

    Drug Metab. Rev.

    (2004)
  • C.A. Lee et al.

    P-glycoprotein-related drug interactions: clinical importance and a consideration of disease states

    Expert Opin. Drug Metab. Toxicol.

    (2010)
  • B. Hagenbuch et al.

    Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties

    Pflugers Arch.

    (2004)
  • N.F. Smith et al.

    Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination

    Expert Opin. Drug Metab. Toxicol.

    (2005)
  • K.M. Giacomini et al.

    Membrane transporters and drug response

  • J. König et al.

    A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane

    Am. J. Physiol. Gastrointest. Liver Physiol.

    (2000)
  • K. Fujiwara et al.

    Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner

    Endocrinology

    (2001)
  • M. Muto et al.

    Human liver-specific organic anion transporter-2 is a potent prognostic factor for human breast carcinoma

    Cancer Sci.

    (2007)
  • L. Li et al.

    Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione

    Mol. Pharmacol.

    (2000)
  • C. Mahagita et al.

    Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport

    Am. J. Physiol. Gastrointest. Liver Physiol.

    (2007)
  • M. Yamazaki et al.

    Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics

    Pharm. Res.

    (1996)
  • W. Mück et al.

    Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients

    Clin. Pharmacol. Ther.

    (1999)
  • Y. Shitara et al.

    In vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats

    Drug Metab. Dispos.

    (2004)
  • W. Mück

    Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions

    Drugs

    (1998)
  • L. Zhang et al.

    Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions

    Mol. Pharm.

    (2009)
  • K.M. Giacomini et al.

    Membrane transporters in drug development

    Nat. Rev. Drug Discov.

    (2010)
  • I. Ieiri et al.

    Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs

    Expert Opin. Drug Metab. Toxicol.

    (2009)
  • S.P.R. Romaine et al.

    The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

    Pharmacogenomics J.

    (2010)
  • The SEARCH Collaborative Group et al.

    SLCO1B1 variants and statin-induced myopathy¯a genomewide study

    N. Engl. J. Med.

    (2008)
  • M.K. Pasanen et al.

    SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid

    Pharmacogenet. Genomics

    (2006)
  • C. Chen et al.

    Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1

    Drug Metab. Dispos.

    (2005)
  • R.C. Hartkoorn et al.

    HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms

    Pharmacogenet. Genomics

    (2010)
  • U. Werner et al.

    Gender is an important determinant of the disposition of the loop diuretic torasemide

    J. Clin. Pharmacol.

    (2010)
  • N. Picard et al.

    The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics

    Clin. Pharmacol. Ther.

    (2010)
  • M. Niemi et al.

    Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1)

    Br. J. Clin. Pharmacol.

    (2005)
  • Cited by (90)

    View all citing articles on Scopus
    View full text