title: Expression of OATP2B1 as determinant of drug effects in the microcompartment of the coronary artery.
abstract: Clinical success of coronary drug-eluting stents (DES) is hampered by simultaneous reduction of smooth muscle cell (HCASMC) and endothelial cell proliferation due to unspecific cytotoxicity of currently used compounds. Previous in vitro data showing SMC-specific inhibition of proliferation suggested that statins may be suitable candidates for DES. It was aim of this study to further investigate statins as DES drug candidates to identify mechanisms contributing to their cell-selectivity. In vitro proliferation assays comparing the influence of various statins on HCASMC and endothelial cells confirmed that atorvastatin exhibits HCASMC-specificity. Due to similar expression levels of the drug target HMG-CoA reductase in both cell types, cellular accumulation of atorvastatin was assessed, revealing enhanced uptake in HCASMC most likely driven by significant expression of OATP2B1, a known uptake transporter for atorvastatin. In accordance with the finding that endogenous OATP2B1 influenced cellular accumulation in HCASMC we used this transporter as a tool to identify teniposide as new DES candidate drug with HCASMC-specific effects. We describe OATP2B1 as a determinant of pharmacokinetics in the coronary artery. Indeed, endogenously expressed OATP2B1 significantly influences the uptake of substrate drugs, thereby governing cell specificity. Screening of candidate drugs for interaction with OATP2B1 may be used to promote SMC-specificity.
authors.affiliation: University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland.
authors.forename: Janine
authors.initials: J
authors.lastname: Hussner
authors.affiliation: University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Begunk
authors.affiliation: University Medicine, Ernst Moritz Arndt University Greifswald, Center of Drug Absorption and Transport, Institute of Pharmacology, Greifswald, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Boettcher
authors.affiliation: University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Gliesche
authors.affiliation: University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Prestin
authors.affiliation: University of Basel, Department of Pharmaceutical Sciences, Biopharmacy, Basel, Switzerland. Electronic address: h.meyerzuschwabedissen@unibas.ch.
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Meyer Zu Schwabedissen
mesh_terms: D000069059:Atorvastatin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D000069059:Atorvastatin
keywords: Atorvastatin; Drug-eluting stents; OATP2B1; Smooth muscle cell-selectivity