Interaction of Oral Antidiabetic Drugs With Hepatic Uptake Transporters

Focus on Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

  1. Iouri Bachmakov,
  2. Hartmut Glaeser,
  3. Martin F. Fromm and
  4. Jörg König
  1. From the Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  1. Corresponding author: Dr. Jörg König, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany. E-mail: joerg.koenig{at}


OBJECTIVE—The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action, their subsequent systemic plasma concentrations, and extrahepatic actions. In vitro and in vivo studies indicate that many drugs used for treatment of cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are taken up into hepatocytes by distinct organic anion transporters (organic anion transporting polypeptides [OATPs]; gene symbol SLCO/SLC21) or organic cation transporters (OCTs; gene symbol SLC22). Because most patients with type 2 diabetes receive more than one drug and inhibition of drug transporters has been recognized as a new mechanism underlying drug-drug interactions, we tested the hypothesis of whether oral antidiabetic drugs can inhibit the transport mediated by hepatic uptake transporters.

RESEARCH DESIGN AND METHODS—Using stably transfected cell systems recombinantly expressing the uptake transporters OATP1B1, OATP1B3, OATP2B1, or OCT1, we analyzed whether the antidiabetic drugs repaglinide, rosiglitazone, or metformin influence the transport of substrates and drugs (for OATPs, sulfobromophthalein [BSP] and pravastatin; for OCT1, 1-methyl-4-phenylpyridinium [MPP+] and metformin).

RESULTS—Metformin did not inhibit the uptake of OATP and OCT1 substrates. However, OATP-mediated BSP and pravastatin uptake and OCT1-mediated MPP+ and metformin uptake were significantly inhibited by repaglinide (half-maximal inhibitory concentration [IC50] 1.6–5.6 μmol/l) and rosiglitazone (IC50 5.2–30.4 μmol/l).

CONCLUSIONS—These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetic drugs have to be considered as potential mechanisms underlying drug-drug interactions.


  • Published ahead of print at on 26 February 2008. DOI: 10.2337/db07-1515.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 21, 2008.
    • Received October 25, 2007.
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  1. Diabetes vol. 57 no. 6 1463-1469
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