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Article

In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors

1
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
2
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
3
Department of Internal Medicine, Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
4
Division of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Authors contributed equally.
Academic Editor: Gert Fricker
Pharmaceutics 2021, 13(12), 2004; https://doi.org/10.3390/pharmaceutics13122004
Received: 16 October 2021 / Revised: 22 November 2021 / Accepted: 23 November 2021 / Published: 25 November 2021
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy. View Full-Text
Keywords: MATE1; TKIs; knockout mice; renal elimination; drug-drug interactions MATE1; TKIs; knockout mice; renal elimination; drug-drug interactions
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MDPI and ACS Style

Uddin, M.E.; Talebi, Z.; Chen, S.; Jin, Y.; Gibson, A.A.; Noonan, A.M.; Cheng, X.; Hu, S.; Sparreboom, A. In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors. Pharmaceutics 2021, 13, 2004. https://doi.org/10.3390/pharmaceutics13122004

AMA Style

Uddin ME, Talebi Z, Chen S, Jin Y, Gibson AA, Noonan AM, Cheng X, Hu S, Sparreboom A. In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors. Pharmaceutics. 2021; 13(12):2004. https://doi.org/10.3390/pharmaceutics13122004

Chicago/Turabian Style

Uddin, Muhammad E., Zahra Talebi, Sijie Chen, Yan Jin, Alice A. Gibson, Anne M. Noonan, Xiaolin Cheng, Shuiying Hu, and Alex Sparreboom. 2021. "In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors" Pharmaceutics 13, no. 12: 2004. https://doi.org/10.3390/pharmaceutics13122004

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