You are here

  • Home
  • Archive
  • Volume 8, Issue 1
  • Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model

Article Text

Article menu

Download PDFPDF

XML
Emerging Technologies, Pharmacology and Therapeutics
Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model
  1. Rene A Posma1,
  2. Leonie H Venema2,
  3. Tobias M Huijink2,
  4. Andrie C Westerkamp2,
  5. A Mireille A Wessels3,
  6. Nynke J De Vries2,
  7. Frank Doesburg1,
  8. J Roggeveld3,
  9. Petra J Ottens2,
  10. Daan J Touw3,
  11. Maarten W Nijsten1,
  12. Henri G D Leuvenink2
  1. 1Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Rene A Posma; r.a.posma{at}umcg.nl

Abstract

Introduction Metformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination.

Research design and methods First, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry.

Results Metformin clearance was approximately 4–5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L.

Conclusions Metformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times.

  • metformin
  • transport
  • pharmacokinetics
  • lactic acidosis
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/bmjdrc-2019-000816

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • Presented at Preliminary data were presented as an abstract at the 30th annual conference of the European Society of Intensive Care Medicine in Vienna, Austria, September 23–27, 2017, and at the International Meeting on Ischemia-Reperfusion Injury in Transplantation, Poitiers, France, April 19–20, 2018.

    • Contributors RAP, TMH and LHV performed experiments, acquired data and wrote the first draft of the manuscript. RAP, LHV, ACW, DJT, MWN and HGDL designed the studies. NJDV, AMAW, JR and PJO performed experiments and acquired data. FD wrote software used in this experiment and provided equipment. All authors revised the manuscript critically for important intellectual content and approved the final version of the manuscript. RAP and HGDL are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses.

    • Funding This work was supported by project grant (2018–36) provided by Stichting De Cock-Hadders to RAP.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study protocol was approved by the Institutional Animal Care and Use Committee of the University of Groningen (DEC-6708C).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement The datasets generated during the current study are available from the corresponding author on reasonable request.