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Organic Ion Transporters and Statin Drug Interactions

  • Statin Drugs (Barbara Wiggins, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Statin drug-drug interactions (DDIs) are both troublesome to patients as well as costly to medical resources. The ability to predict and avoid these events could lead to improved outcomes as well as patient satisfaction. This review will explore efforts to better understand and predict these interactions specifically related to one drug transport system, the organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and OATP1B3.

Recent Findings

Since the publication of the discovery of OATPs, there have been various pharmacokinetic models that have been proposed to explain the variation in pharmacokinetic and clinical effects related to the OATPs. The effects in transport activity appear to be partially related to the individual polymorphisms studied. Drug-drug interactions can occur when other drugs compete for the metabolic site on the OATPs. Various medications are identified as substrates and/or inhibitors of the OATPs, thereby complicating the ability to fully predict the impact on levels and effects. All of the models reviewed claim successes but show limited clinical utility.

There are specific populations that have been identified, predominately various Asian descendants that require lower doses of statins to avoid adverse events. The concept of attributing these actions to the OATPs has been explored, but current models cannot accurately predict statin blood levels or elimination constants. The current research only points to the differences in the human genome and the single-nucleotide polymorphisms that exist between us.

Summary

Based upon the currently available studies, there is beginning to be a glimmer in the understanding how different populations respond to statin transport and elimination. Additionally and unfortunately, there are other enzymes to be studied to better predict patient differences. Clearly, there has been much work completed, yet many more questions require answering to better understand these transport proteins.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Konig J, Cui Y, Nies AT, Keppler D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000;275(30):23161–8. https://doi.org/10.1074/jbc.M001448200.

    Article  CAS  PubMed  Google Scholar 

  2. • The International Transporter Consortium, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36. https://doi.org/10.1038/nrd3028. This essential reference provides a background overview of various transporters and their role in drug metabolism. This will serve as a primer for learners interested in how transporters work and potential study design for better understanding their effect.

  3. Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999;274(52):37161–8.

    Article  CAS  PubMed  Google Scholar 

  4. Colombo D, Lunardon L, Bellia G. Cyclosporine and herbal supplement interactions. J Toxicol. 2014;2014:145325. https://doi.org/10.1155/2014/145325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harper CR, Jacobson TA. Avoiding statin myopathy: understanding key drug interactions. Clin Lipidol. 2011;6:665–74.

    Article  CAS  Google Scholar 

  6. Kellick KA, Bottorff M, Toth PP, The National Lipid Association’s Safety Task F. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol. 2014;8(3 Suppl):S30–46. https://doi.org/10.1016/j.jacl.2014.02.010.

    Article  PubMed  Google Scholar 

  7. •• Prasad B, Evers R, Gupta A, Hop CE, Salphati L, Shukla S, et al. Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metab Dispos. 2014;42(1):78–88. https://doi.org/10.1124/dmd.113.053819. The article reveals a prediction methodology for patients taking rosuvastatin.. using frozen liver hepatocytes in a small number of samples,/ Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Using a in vitro prediction role, there was some ability to predict AUC changes with rosuvastatin.

  8. Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem. 2001;276(38):35669–75. https://doi.org/10.1074/jbc.M103792200.

    Article  CAS  PubMed  Google Scholar 

  9. Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73(6):554–65. https://doi.org/10.1016/S0009-9236(03)00060-2.

    Article  CAS  PubMed  Google Scholar 

  10. Administration USFaD. Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. In: Communication FDA, 2011–2017.

  11. Li R, Barton HA, Yates PD, Ghosh A, Wolford AC, Riccardi KA, et al. A “middle-out” approach to human pharmacokinetic predictions for OATP substrates using physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn. 2014;41(3):197–209. https://doi.org/10.1007/s10928-014-9357-1.

    Article  CAS  PubMed  Google Scholar 

  12. Li R, Barton HA. Explaining ethnic variability of transporter substrate pharmacokinetics in healthy Asian and Caucasian subjects with allele frequencies of OATP1B1 and BCRP: a mechanistic modeling analysis. Clin Pharmacokinet. 2017; https://doi.org/10.1007/s40262-017-0568-7.

  13. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81. https://doi.org/10.1124/pr.110.002857.

    Article  CAS  PubMed  Google Scholar 

  14. •• Yee SW, Giacomini MM, Hsueh CH, Weitz D, Liang X, Goswami S, et al. Metabolomic and genome-wide association studies reveal potential endogenous biomarkers for OATP1B1. Clin Pharmacol Ther. 2016;100(5):524–36. https://doi.org/10.1002/cpt.434. This study explored various metabolites that interfere with OATP1B1. The group revealed potential biomarkers that can be used during drug development to possibly better predict drug-drug interactions mediated by OATP1B1.

  15. Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, et al. Quantitative analyses of hepatic OATP-mediated interactions between statins and inhibitors using PBPK modeling with a parameter optimization method. Clin Pharmacol Ther. 2016;100(5):513–23. https://doi.org/10.1002/cpt.391.

    Article  CAS  PubMed  Google Scholar 

  16. Patilea-Vrana G, Unadkat JD. Transport vs. metabolism: what determines the pharmacokinetics and pharmacodynamics of drugs? Insights from the extended clearance model. Clin Pharmacol Ther. 2016;100(5):413–8. https://doi.org/10.1002/cpt.437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Khine H, Yuet WC, Adams-Huet B, Ahmad Z. Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia. Am Heart J. 2016;179:1–9. https://doi.org/10.1016/j.ahj.2016.05.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. VA Western NY Healthcare System, Buffalo, USA

    Kenneth Kellick

  2. State University of New York at Buffalo, Buffalo, USA

    Kenneth Kellick

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  1. Kenneth Kellick
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Correspondence to Kenneth Kellick.

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Kenneth Kellick declares no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is a part of the Topical Collection on Statin Drugs

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Kellick, K. Organic Ion Transporters and Statin Drug Interactions. Curr Atheroscler Rep 19, 65 (2017). https://doi.org/10.1007/s11883-017-0701-y

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  • DOI: https://doi.org/10.1007/s11883-017-0701-y

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