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

  • Pharmacokinetics and Disposition
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Abstract

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 K i 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 (r S = 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.

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Acknowledgments

Data presented in this work are part of the doctoral thesis of C.A.P.

Conflict of interest

F.M. holds a minor share of stock in Novartis, received research funding from Sanofi-Aventis Deutschland, and started working as an employee of Boehringer Ingelheim Pharma GmbH & Co. KG after the analysis and interpretation of data presented in this manuscript were finished. M.F.F. reported receiving personal compensation for expert testimony from Boehringer Ingelheim Pharma and payments for lectures from Bayer-Schering Pharma, Sanofi-Aventis Deutschland, and Merck KGaA. M.F.F.’s institution received compensation for commissioned research of his group from Merck KGaA and Sanofi-Aventis Deutschland and for supply for in vitro studies from Gilead.

Author contribution statement

F.M., C.A.P., M.M., B.R., and M.F.F. wrote the manuscript. F.M., M.M., D.A., R.M., O.Z., and M.F.F. designed the research study. F.M., C.A.P., M.M., E.H., D.A., O.Z., and M.F.F. performed the research. F.M., C.A.P., B.R., and M.F.F. analyzed the data.

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Correspondence to Martin F. Fromm.

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Müller, F., Pontones, C.A., Renner, B. et al. N1-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin–trimethoprim interaction. Eur J Clin Pharmacol 71, 85–94 (2015). https://doi.org/10.1007/s00228-014-1770-2

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