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Differences in metformin and thiamine uptake between human and mouse organic cation transporter OCT1: structural determinants and potential consequences for intrahepatic concentrations

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jurgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition October 9, 2020, DMD-AR-2020-000170; DOI: https://doi.org/10.1124/dmd.120.000170
Marleen J. Meyer
1Institute of Pharmacology, University Medicine Greifswald, Center of Drug Absorption and Transport (C_DAT), Germany
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Alzbeta Tuerkova
2Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Austria
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Sarah Römer
1Institute of Pharmacology, University Medicine Greifswald, Center of Drug Absorption and Transport (C_DAT), Germany
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Christoph Wenzel
1Institute of Pharmacology, University Medicine Greifswald, Center of Drug Absorption and Transport (C_DAT), Germany
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Tina Seitz
3Institute of Clinical Pharmacology, University Medical Center Göttingen, Germany
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Jochen Gaedcke
4Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Germany
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Stefan Oswald
5Department of Pharmacology, Rostock University Medical Center, Germany
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Jurgen Brockmöller
6Germany
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Barbara Zdrazil
7Department of Pharmaceutical Chemistry, University of Vienna, Austria
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  • ORCID record for Barbara Zdrazil
Mladen V. Tzvetkov
1Institute of Pharmacology, University Medicine Greifswald, Center of Drug Absorption and Transport (C_DAT), Germany
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  • For correspondence: mladen.tzvetkov@med.uni-greifswald.de
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Abstract

The most commonly used oral antidiabetic drug metformin is a substrate of the hepatic uptake transporter OCT1 (SLC22A1). However, OCT1 deficiency leads to more pronounced reductions of metformin concentrations in mouse than in human liver. Similarly, the effects of OCT1 deficiency on the pharmacokinetics of thiamine were reported to differ between human and mouse. Here, we compared the uptake characteristics of metformin and thiamine between human and mouse OCT1 using stably transfected HEK293 cells. The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, resulting in a 6.5-fold lower intrinsic clearance. Therefore, the estimated liver-to-blood partition coefficient is only 3.34 in human compared to 14.4 in mouse and may contribute to higher intrahepatic concentrations in mice. Similarly, the affinity for thiamine was 9.5-fold lower in human than in mouse OCT1. Using human-mouse chimeric OCT1 we showed that simultaneous substitution of transmembrane helices TMH2 and TMH3 resulted in the reversal of affinity for metformin. Using homology modelling we suggest several explanations, of which a different interaction of Leu155 (human TMH2) compared to Val156 (mouse TMH2) with residues in TMH3 had the strongest experimental support. In conclusion, the contribution of human OCT1 to the cellular uptake of thiamine and especially of metformin may be much lower than that of mouse OCT1. This may lead to an overestimation of the effects of OCT1 on hepatic concentrations in humans when using mouse as a model. In addition, comparative analyses of human and mouse orthologs may help reveal mechanisms of OCT1 transport.

Significance Statement OCT1 is a major hepatic uptake transporter of metformin and thiamine, but we report strong differences in the affinity for both compounds between human and mouse OCT1. Consequently, intrahepatic metformin concentrations could be much higher in mice than in humans, impacting metformin actions and representing a strong limitation of using rodent animal models for predictions of OCT1-related pharmacokinetics and efficacy in humans. Furthermore, OCT1 transmembrane helices TMH2 and TMH3 were identified to confer the observed species-specific differences in metformin affinity.

  • Organic cation uptake / efflux (OCTs, ENTs)
  • Structure-activity relationships and modeling
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Human and mouse OCT1 differ in metformin and thiamine uptake

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jurgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition October 9, 2020, DMD-AR-2020-000170; DOI: https://doi.org/10.1124/dmd.120.000170

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Human and mouse OCT1 differ in metformin and thiamine uptake

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jurgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition October 9, 2020, DMD-AR-2020-000170; DOI: https://doi.org/10.1124/dmd.120.000170
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