Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin

Clin Pharmacol Ther. 2016 Sep;100(3):259-67. doi: 10.1002/cpt.406. Epub 2016 Jul 29.

Abstract

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P-gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2-K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six-period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0-tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0-tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter-mediated drug-drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • ATP-Binding Cassette Transporters / metabolism*
  • Adult
  • Area Under Curve
  • Cation Transport Proteins / metabolism*
  • Cross-Over Studies
  • Digoxin / pharmacokinetics*
  • Digoxin / pharmacology
  • Drug Interactions
  • Furosemide / pharmacokinetics*
  • Furosemide / pharmacology
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Male
  • Metabolic Clearance Rate
  • Metformin / pharmacokinetics*
  • Metformin / pharmacology
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Organic Anion Transport Protein 1 / metabolism
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Organic Cation Transport Proteins / metabolism
  • Organic Cation Transporter 2
  • Rosuvastatin Calcium / pharmacokinetics*
  • Rosuvastatin Calcium / pharmacology
  • Solute Carrier Organic Anion Transporter Family Member 1B3

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Cation Transport Proteins
  • Liver-Specific Organic Anion Transporter 1
  • Neoplasm Proteins
  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • SLC47A1 protein, human
  • SLC47A2 protein, human
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • organic anion transport protein 3
  • Digoxin
  • Furosemide
  • Rosuvastatin Calcium
  • Metformin