title: The Nonmetabolized β-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3.
abstract: Nadolol is a nonmetabolized β-adrenoceptor antagonist and is a substrate of OATP1A2, but not of OATP2B1. However, other drug transporters involved in translocation of nadolol have not been characterized in detail. We therefore investigated nadolol as a potential substrate of the hepatic uptake transporters OATP1B1, OATP1B3, and OCT1 and of the renal transporters OCT2, MATE1, and MATE2-K expressed in HEK cells. Moreover, the importance of P-glycoprotein (P-gp) for nadolol transport was studied using double transfected MDCK-OCT1-P-gp cells. Nadolol was not transported by OATP1B1 and OATP1B3. In contrast, a significantly higher nadolol accumulation (at 1 and 10 μM) was found in OCT1, OCT2, MATE1, and MATE2-K cells compared to control cells (P < 0.01). Km values for OCT2-, MATE1-, and MATE2-K-mediated nadolol uptake were 122, 531, and 372 μM, respectively. Cimetidine (100 μM, P < 0.01) and trimethoprim (100 μM, P < 0.001) significantly inhibited OCT1-, OCT2-, MATE1-, and MATE2-K-mediated nadolol transport. The P-gp inhibitor zosuquidar significantly reduced basal to apical nadolol transport in monolayers of MDCK-OCT1-P-gp cells. In summary, nadolol is a substrate of the cation transporters OCT1, OCT2, MATE1, MATE2-K, and of P-gp. These data will aid future in vivo studies on potential transporter-mediated drug-drug or drug-food interactions with involvement of nadolol.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.|Department of Pharmacology, School of Medicine, Fukushima Medical University , Fukushima, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Knop
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Singer
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoier
authors.affiliation: Department of Clinical Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald , Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Keiser
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Glaeser
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D009248:Nadolol / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D009248:Nadolol
keywords: P-glycoprotein; metformin; multidrug and toxin extrusion protein (MATE); nadolol; organic anion transporting polypeptide (OATP); organic cation transporter (OCT)