title: Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters.
abstract: OBJECTIVE
  Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.
  
  
  METHODS
  Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.
  
  
  RESULTS
  In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016).
  
  
  CONCLUSIONS
  The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grün
authors.forename: Michael K
authors.initials: MK
authors.lastname: Kiessling
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rauch
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.forename: David
authors.initials: D
authors.lastname: Czock
mesh_terms: D000328:Adult; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000494:pharmacology; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood / Q000652:urine; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide; D014295:Trimethoprim / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000892:Anti-Infective Agents, Urinary; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D019344:Lactic Acid; D008687:Metformin; D014295:Trimethoprim; D003404:Creatinine
keywords: drug interaction; genetic polymorphism; metformin; pharmacokinetics; trimethoprim