title: N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction.
abstract: OBJECTIVE
  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.
  
  
  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 N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Constanza A
authors.initials: CA
authors.lastname: Pontones
authors.forename: Bertold
authors.initials: B
authors.lastname: Renner
authors.forename: Maren
authors.initials: M
authors.lastname: Mieth
authors.forename: Eva
authors.initials: E
authors.lastname: Hoier
authors.forename: Daniel
authors.initials: D
authors.lastname: Auge
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D014295:Trimethoprim / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D009536:Niacinamide; D008687:Metformin; D014295:Trimethoprim; D003404:Creatinine; C024058:N(1)-methylnicotinamide