N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction

Mueller F, Pontones C, Renner B, Mieth M, Hoier E, Auge D, Maas R, Zolk O, Fromm M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

European Journal of Clinical Pharmacology Springer Verlag (Germany)

Book Volume: 71

Pages Range: 85-94

Journal Issue: 1

DOI: 10.1007/s00228-014-1770-2

Abstract

N(1)-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.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.Trimethoprim inhibited metformin transport with K i values of 27.2, 6.3, and 28.9 ?M and NMN transport with IC50 values of 133.9, 29.1, and 0.61 ?M 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).These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.

Authors with CRIS profile

Constanza Pontones Department of Obstetrics and Gynaecology Bertold Renner Lehrstuhl für Pharmakologie und Toxikologie Maren Mieth Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Daniel Auge Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Renke Maas Professur für Arzneimitteltherapiesicherheit und Klinische Pharmakologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Universität Ulm DE Germany (DE)

How to cite

APA:

Mueller, F., Pontones, C., Renner, B., Mieth, M., Hoier, E., Auge, D.,... Fromm, M. (2015). N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction. European Journal of Clinical Pharmacology, 71(1), 85-94. https://dx.doi.org/10.1007/s00228-014-1770-2

MLA:

Mueller, Fabian, et al. "N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction." European Journal of Clinical Pharmacology 71.1 (2015): 85-94.

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