The Nonmetabolized beta-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3.

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Misaka S, Knop J, Singer K, Hoier E, Keiser M, Muller F, Glaeser H, Konig J, Fromm MF

The Nonmetabolized beta-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3.

Mol Pharm. 2016 Feb 1;13(2):512-9. doi: 10.1021/acs.molpharmaceut.5b00733. Epub 2016 Jan 19.

PubMed ID

26702643 [ View in PubMed

]

Abstract

Nadolol is a nonmetabolized beta-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 muM) 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 muM, respectively. Cimetidine (100 muM, P < 0.01) and trimethoprim (100 muM, 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.

DrugBank Data that Cites this Article

Drugs

Trimethoprim

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Nadolol	Multidrug and toxin extrusion protein 1	Protein	Humans	Unknown	Substrate	Details
Nadolol	Multidrug and toxin extrusion protein 2	Protein	Humans	Unknown	Substrate	Details
Nadolol	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details
Nadolol	POU domain, class 2, transcription factor 1	Protein	Humans	Unknown	Substrate	Details
Nadolol	POU domain, class 2, transcription factor 2	Protein	Humans	Unknown	Substrate	Details
Trimethoprim	Multidrug and toxin extrusion protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Trimethoprim	Multidrug and toxin extrusion protein 2	Protein	Humans	Unknown	Substrate Inhibitor	Details