In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects

J Clin Pharmacol. 2011 May;51(5):761-9. doi: 10.1177/0091270010376193. Epub 2010 Aug 2.

Abstract

Interactions between tolvaptan and digoxin were determined in an open-label, sequential study where 14 healthy subjects received tolvaptan 60 mg once daily (QD) on days 1 and 12 to 16 and digoxin 0.25 mg QD on days 5 to 16. Mean maximal concentrations (C(max)) and area under the curve during the dosing interval (AUC(τ)) for digoxin with tolvaptan (day 16) were increased 1.27- and 1.18-fold compared with digoxin alone (day 11); mean renal clearance of digoxin was decreased by 59% (P < .05). Tolvaptan C(max) and AUC(0-24h) for a single dose with digoxin (day 12) were each increased about 10% compared with tolvaptan alone (day 1). Tolvaptan did not accumulate upon multiple dosing. After a single dose of tolvaptan (day 1, day 12), 24-hour urine volume was about 7.5 L. As expected, after 5 days of tolvaptan, 24-hour urine volume decreased about 20%. In vitro studies in control and MDR1-expressing LLC-PK1 cells indicate that tolvaptan is a substrate of P-glycoprotein. Tolvaptan (50 µM) inhibited basolateral to apical digoxin secretion to the same extent as 30 µM verapamil; the IC50 of tolvaptan was determined to be 15.9 µM. The increase in steady-state digoxin concentrations is likely mediated by tolvaptan inhibition of digoxin secretion.

Publication types

  • Clinical Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Administration, Oral
  • Adolescent
  • Adult
  • Analysis of Variance
  • Animals
  • Antidiuretic Hormone Receptor Antagonists
  • Area Under Curve
  • Benzazepines / administration & dosage
  • Benzazepines / blood
  • Benzazepines / pharmacokinetics*
  • Benzazepines / urine
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / blood
  • Cardiotonic Agents / pharmacokinetics*
  • Cardiotonic Agents / urine
  • Digoxin / administration & dosage
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Digoxin / urine
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Florida
  • Hormone Antagonists / administration & dosage
  • Hormone Antagonists / blood
  • Hormone Antagonists / pharmacokinetics*
  • Hormone Antagonists / urine
  • Humans
  • LLC-PK1 Cells
  • Male
  • Metabolic Clearance Rate
  • Models, Biological
  • Swine
  • Tolvaptan
  • Transfection
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • Cardiotonic Agents
  • Hormone Antagonists
  • Tolvaptan
  • Digoxin