N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: Studies on the metformin-trimethoprim interaction

Research output: Contribution to journalResearch articleContributedpeer-review


  • Fabian Müller - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Constanza A. Pontones - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Bertold Renner - , Institute of Clinical Pharmacology, Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Maren Mieth - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Eva Hoier - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Daniel Auge - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Renke Maas - , Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Oliver Zolk - , Ulm University (Author)
  • Martin F. Fromm - , Friedrich-Alexander University Erlangen-Nürnberg (Author)


Purpose: N1-methylnicotinamide (NMN) was proposed as an in vivo probe for drug interactions involving renal cation transporters, which, for example, transport the oral antidiabetic drug metformin, based on a study with the inhibitor pyrimethamine. The role of NMN for predicting other interactions with involvement of renal cation transporters (organic cation transporter 2, OCT2; multidrug and toxin extrusion proteins 1 and 2-K, MATE1 and MATE2-K) is unclear. Methods: We determined inhibition of metformin or NMN transport by trimethoprim using cell lines expressing OCT2, MATE1, or MATE2-K. Moreover, a randomized, open-label, two-phase crossover study was performed in 12 healthy volunteers. In each phase, 850 mg metformin hydrochloride was administered p.o. in the evening of day 4 and in the morning of day 5. In phase B, 200 mg trimethoprim was administered additionally p.o. twice daily for 5 days. Metformin pharmacokinetics and effects (measured by OGTT) and NMN pharmacokinetics were determined. Results: Trimethoprim inhibited metformin transport with Ki values of 27.2, 6.3, and 28.9 μM and NMN transport with IC50 values of 133.9, 29.1, and 0.61 μM for OCT2, MATE1, and MATE2-K, respectively. In the clinical study, trimethoprim increased metformin area under the plasma concentration-time curve (AUC) by 29.5 % and decreased metformin and NMN renal clearances by 26.4 and 19.9 %, respectively (p≤0.01). Moreover, decreases of NMN and metformin renal clearances due to trimethoprim correlated significantly (rS=0.727, p=0.010). Conclusions: These data on the metformin-trimethoprim interaction support the potential utility of N1-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.


Original languageEnglish
Pages (from-to)85-94
Number of pages10
JournalEuropean journal of clinical pharmacology
Issue number1
Publication statusPublished - Jan 2015

External IDs

PubMed 25552403
ORCID /0000-0003-0845-6793/work/139025190


ASJC Scopus subject areas


  • MATE1, Multidrug and toxin extrusion protein, N-methylnicotinamide, NMN, OCT2, OGTT, Oral glucose tolerance test, Organic cation transporter 2