title: The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers.
abstract: OBJECTIVE
  Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin.
  
  
  METHODS
  Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max).
  
  
  RESULTS
  In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions.
  
  
  CONCLUSIONS
  Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs.
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: El Messaoudi
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F G
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Colbers
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: C C J G
authors.initials: CC
authors.lastname: Bandell
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: P H H
authors.initials: PH
authors.lastname: van den Broek
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: Burger
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Internal Medicine 463, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Rongen
authors.affiliation: Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands. niels.riksen@radboudumc.nl.|Department of Internal Medicine 463, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. niels.riksen@radboudumc.nl.
authors.forename: N P
authors.initials: NP
authors.lastname: Riksen
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004176:Dipyridamole / Q000009:adverse effects / Q000494:pharmacology*; D033705:Equilibrative Nucleoside Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D033705:Equilibrative Nucleoside Transport Proteins; D007004:Hypoglycemic Agents; D010975:Platelet Aggregation Inhibitors; C495988:SLC29A4 protein, human; D004176:Dipyridamole; D008687:Metformin
keywords: Dipyridamole; Drug interaction; ENT4; Metformin; PMAT; Pharmacokinetics