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 b-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 b-blockers. Rosuvastatin transport was saturable, with a K m of 60.2 mM. With the exception of carvedilol (IC 50 of 3.2 mM), all of the other b-blockers that were evaluated had a small or insignificant effect on OATP1A2-mediated uptake of rosuvastatin. Carvedilol differs from the other b-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.

BackgroundOATP1A2 is a membrane transporter potentially involved in the absorption of various drugs. Previous data demonstrated that the uptake of rosuvastatin through OATP1A2 can be inhibited by several β‐blockers, where carvedilol is the most potent inhibitor. Carvedilol structurally differs from the other β‐blockers tested by its tricyclic moiety. The goal of this study was to determine whether the tricyclic structure of carvedilol is responsible for its strong inhibitory effect on OATP1A2.MethodsA HEK293 cell line overexpressing OATP1A2 was used as model. They were co‐incubated in the presence of rosuvastatin and increasing concentrations of different tricyclic compounds. The amount of rosuvastatin transported in the cells was measured by HPLC.ResultsMost tricyclic compounds evaluated inhibited rosuvastatin uptake through OATP1A2 with different IC50. Our data show that the inhibition is competitive. Compound IC50 (μM) Compound IC50 (μM) carazolol 4.0 nortriptyline 14.8 amitriptyline 5.0 chlorpromazine 29.6 imipramine 12.6 desipramine 77.9 trimipramine 13.6 carbamazepine >;100 doxepin 14.0 carbazole No effect clomipramine 14.7 phenothiazine No effect ConclusionsThe inhibitory component is made up of the tricyclic ring with a short aliphatic chain. Consequently, drugs with a similar structure may strongly modulate the transport of OATP1A2 substrates.Funding: CIHR, FRSQ, Foundation CHUM