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

Misaka S, Knop J, Singer K, Hoier E, Keiser M, Müller F, Gläser H, König J, Fromm M (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Molecular Pharmaceutics American Chemical Society

Book Volume: 13

Pages Range: 512-9

Journal Issue: 2

DOI: 10.1021/acs.molpharmaceut.5b00733

Abstract

Nadolol is a nonmetabolized ?-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 ?M) 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 ?M, respectively. Cimetidine (100 ?M, P < 0.01) and trimethoprim (100 ?M, 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 with CRIS profile

Jana Knop Lehrstuhl für Biochemie und Pathobiochemie Katrin Singer Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Eva Hoier Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Fabian Müller Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Hartmut Gläser Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Jörg König Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Universitätsmedizin Greifswald / Universitätsklinikum Greifswald DE Germany (DE)

How to cite

APA:

Misaka, S., Knop, J., Singer, K., Hoier, E., Keiser, M., Müller, F.,... Fromm, M. (2016). The Nonmetabolized β-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3. Molecular Pharmaceutics, 13(2), 512-9. https://doi.org/10.1021/acs.molpharmaceut.5b00733

MLA:

Misaka, Shingen, et al. "The Nonmetabolized β-Blocker Nadolol Is a Substrate of OCT1, OCT2, MATE1, MATE2-K, and P-Glycoprotein, but Not of OATP1B1 and OATP1B3." Molecular Pharmaceutics 13.2 (2016): 512-9.

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