Abstract

The organic anion transporting polypeptide 1A2 (OATP1A2), a membrane drug transporter expressed on important organs (such as the brain, kidney, and intestine) may be a key element in the disposition of drugs. Previous studies demonstrated that it could transport a broad spectrum of substrates, including endogenous molecules and clinically relevant drugs, such as several β-blockers and 3-hydroxy-3-methylglutaryl–CoA reductase inhibitors. The primary objective of this study was to investigate OATP1A2 transport activity using rosuvastatin as a probe substrate and evaluate competitive inhibition of its transport by β-blockers. Rosuvastatin transport was saturable, with a K_m of 60.2 µM. With the exception of carvedilol (IC₅₀ of 3.2 µM), all of the other β-blockers that were evaluated had a small or insignificant effect on OATP1A2-mediated uptake of rosuvastatin. Carvedilol differs from the other β-blockers by the tricyclic moiety in its chemical structure. As a secondary objective, the transport of a series of tricyclic compounds by OATP1A2 and their potential for rosuvastatin transport inhibition were evaluated. Tricyclic compounds were not OATP1A2 substrates. On the other hand, tricyclic compounds with a short aliphatic amine chain inhibited OATP1A2-mediated rosuvastatin transport. Our data suggest that these drugs may modulate the transport of OATP1A2 substrates and may affect drug actions.