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Drug Metabolism and Disposition Fast Forward
First published on February 23, 2009; DOI: 10.1124/dmd.108.024570

0090-9556/09/3705-1129-1137$20.00
DMD 37:1129-1137, 2009

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Human Platelets Express Organic Anion-Transporting Peptide 2B1, an Uptake Transporter for Atorvastatin

Juliane Niessen, Gabriele Jedlitschky, Markus Grube, Sandra Bien, Hansjörg Schwertz, Sumio Ohtsuki, Hirotaka Kawakami, Junichi Kamiie, Stefan Oswald, Katharina Starke, Ulrike Strobel, Werner Siegmund, Dieter Rosskopf, Andreas Greinacher, Tetsuya Terasaki, and Heyo K. Kroemer

Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics (J.N., G.J., M.G., S.B., S.Oh., K.S., W.S., D.R., H.K.K.), Department of Immunology and Transfusion Medicine (U.S., A.G.), Ernst-Moritz-Arndt-University, Greifswald, Germany; Department of Surgery and the Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah (H.S.); and Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan (S.Os., H.K., J.K., T.T.)

Statins are widely used to treat dyslipidemia. Effects of statins in addition to low-density lipoprotein lowering include altered platelet aggregation, requiring drug uptake into platelets. Possible candidates for mediating intraplatelet accumulation of statins include members of the organic anion-transporting polypeptide family such as OATP2B1 (SLCO2B1), a high-affinity uptake transporter for atorvastatin. Therefore, we analyzed OATP expression, localization, and function in human platelets. OATP2B1, but not OATP1B1, was detected in platelets and megakaryocytes on transcript and protein levels. Protein localization was almost exclusively confined to the plasma membrane. Moreover, we could demonstrate significant inhibition of estrone sulfate uptake into platelets by atorvastatin as well as direct transport of atorvastatin into platelets using a liquid chromatography-tandem mass spectrometry method. As a consequence of OATP2B1-mediated uptake of atorvastatin, we observed significant atorvastatin-mediated reduction of thrombin-induced Ca2+ mobilization in platelets (37.3 ± 6.7% of control at 15 µM atorvastatin), mechanistically explainable by reduced lipid modification of signal proteins. This effect was reversed by addition of mevalonate. Finally, we demonstrated expression of HMG-CoA reductase, the primary target of atorvastatin, in platelet cytosol. In conclusion, OATP2B1 is an uptake transporter expressed in platelets and is involved in statin-mediated alteration of platelet aggregation.

Address correspondence to: Dr. Heyo K. Kroemer, Department of Pharmacology, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Str. 23 D, D-17487 Greifswald, Germany. E-mail: kroemer{at}uni-greifswald.de






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