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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Administration, Oral
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Adolescent
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Adult
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Analysis of Variance
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Animals
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Antidiuretic Hormone Receptor Antagonists
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Area Under Curve
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Benzazepines / administration & dosage
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Benzazepines / blood
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Benzazepines / pharmacokinetics*
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Benzazepines / urine
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Cardiotonic Agents / administration & dosage
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Cardiotonic Agents / blood
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Cardiotonic Agents / pharmacokinetics*
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Cardiotonic Agents / urine
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Digoxin / administration & dosage
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Digoxin / blood
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Digoxin / pharmacokinetics*
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Digoxin / urine
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Drug Administration Schedule
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Drug Interactions
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Female
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Florida
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Hormone Antagonists / administration & dosage
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Hormone Antagonists / blood
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Hormone Antagonists / pharmacokinetics*
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Hormone Antagonists / urine
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Humans
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LLC-PK1 Cells
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Male
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Metabolic Clearance Rate
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Models, Biological
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Swine
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Tolvaptan
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Transfection
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Young Adult
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antidiuretic Hormone Receptor Antagonists
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Benzazepines
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Cardiotonic Agents
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Hormone Antagonists
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Tolvaptan
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Digoxin