RT Journal Article
SR Electronic
T1 Human Platelets Express Organic Anion-Transporting Peptide 2B1, an Uptake Transporter for Atorvastatin
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1129
OP 1137
DO 10.1124/dmd.108.024570
VO 37
IS 5
A1 Juliane Niessen
A1 Gabriele Jedlitschky
A1 Markus Grube
A1 Sandra Bien
A1 Hansjörg Schwertz
A1 Sumio Ohtsuki
A1 Hirotaka Kawakami
A1 Junichi Kamiie
A1 Stefan Oswald
A1 Katharina Starke
A1 Ulrike Strobel
A1 Werner Siegmund
A1 Dieter Rosskopf
A1 Andreas Greinacher
A1 Tetsuya Terasaki
A1 Heyo K. Kroemer
YR 2009
UL http://dmd.aspetjournals.org/content/37/5/1129.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics