Abstract
The transporter-mediated uptake of drugs from blood into hepatocytes is a prerequisite for intrahepatic drug action or intracellular drug metabolism before excretion. Therefore, uptake transporters, e.g., members of the organic anion transporting polypeptide (OATP) family are important determinants of drug pharmacokinetics. Highly and almost exclusively expressed in hepatocytes are the OATP family members OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Drug substrates of OATP1B1 and OATP1B3 include antibiotics and HMG-CoA reductase inhibitors (statins). It has been demonstrated that administration of two or more drugs that are substrates for these hepatic uptake transporters may lead to transporter-mediated drug-drug interactions, resulting in altered transport kinetics for drug substrates. In this study we investigated whether non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol interact with OATP1B1 and OATP1B3 using the standard substrate BSP and the drug substrate pravastatin. Using human embryonic kidney cells stably expressing OATP1B1 or OATP1B3, we demonstrated that bromosulfophthalein uptake was inhibited by diclofenac, ibuprofen. and lumiracoxib. Of interest, pravastatin uptake was stimulated by these NSAIDs, and for ibuprofen we determined activation constants (EC50 values) of 64.0 and 93.1 μM for OATP1B1- and OATP1B3-mediated uptake, respectively. Furthermore, we investigated whether NSAIDs were also substrates for OATP1B1 and OATP1B3 and demonstrated that only diclofenac was significantly transported by OATP1B3, whereas all other NSAIDs investigated were not substrates for these uptake transporters. These results demonstrated that drugs may interact with transport proteins by allosteric mechanisms without being substrates and, therefore, not only uptake inhibition but also allosteric-induced modulation of transport function may be an important mechanism in transporter-mediated drug-drug interactions.
Footnotes
This work was supported by the Deutsche Krebshilfe [Grant 107854]; and the Deutsche Forschungsgemeinschaft [Grant DFG Ko 2120/1-3].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037622.
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ABBREVIATIONS:
- SLC
- solute carrier
- OATP/Oatp
- organic anion transporting polypeptide
- NSAID
- non-steroidal anti-inflammatory drug
- BSP
- sulfobromophthalein
- MTT
- 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- LC
- liquid chromatography
- HEK
- human embryonic kidney
- MDCK
- Madin-Darby canine kidney
- MS/MS
- tandem mass spectrometry.
- Received December 7, 2010.
- Accepted March 9, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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