OATP2B1 as a Determinant of Drug Effects in The Microcompartment of The Coronary Artery

The implantation of drug‐eluting stents (DES) is a common therapy for atherosclerotic occlusions whereby the loaded compounds often exhibit unspecific cytotoxicity. In detail, clinical success is hampered by simultaneous reduction of smooth muscle (SMC) and endothelial cell proliferation, the latter being associated with reduced endothelialization resulting in prothrombotic surfaces. It was aim of this study to investigate statins as DES candidates to identify mechanisms contributing to a previously reported cell‐selectivity. In vitro proliferation assays confirmed the SMC‐specific activity of atorvastatin. 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 SMCs most likely driven by significant expression of OATP2B1, a transporter known to be involved in pharmacokinetics. The higher accumulation of atorvastatin and its associated specific effect in SMCs was further confirmed by data demonstrating enhanced sensitivity of SMCs overexpressing OATP2B1. In accordance with the finding that endogenous OATP2B1 influenced cellular accumulation of atorvastatin we used this transporter to identify the alkaloid teniposide as new DES candidate that exerts enhanced antiproliferative activity in SMCs. In conclusion, we describe OATP2B1 as a determinant of the pharmacokinetics in SMC of the coronary artery. Indeed, endogenously expressed OATP2B1 significantly influences the uptake of substrate drugs, thereby governing cell specificity. Screening of drugs for interaction with OATP2B1 may be used to promote SMC‐specificity of new drug candidates.