title: Effects of β-blockers and tricyclic antidepressants on the activity of human organic anion transporting polypeptide 1A2 (OATP1A2).
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 Km 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.
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.).
authors.forename: Veronique
authors.initials: V
authors.lastname: Michaud
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.).
authors.forename: Liliam Gabriela Guilarte
authors.initials: LG
authors.lastname: Moya
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.).
authors.forename: Fleur
authors.initials: F
authors.lastname: Gaudette
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.).
authors.forename: Yat Hei
authors.initials: YH
authors.lastname: Leung
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., F.G., Y.H.L., J.T.); and Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada (J.L., V.M., L.G.G.M., Y.H.L., J.T.) jacques.turgeon.chum@ssss.gouv.qc.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Turgeon
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D000929:Antidepressive Agents, Tricyclic; D027361:Organic Anion Transporters; C512988:SLCO1A2 protein, human