title: In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects.
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.
authors.affiliation: Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, Maryland, USA. Susan.Shoaf@otsuka-us.com
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohzone
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Furukawa
authors.forename: Patricia
authors.initials: P
authors.lastname: Bricmont
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiyama
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005431:Florida; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D018374:LLC-PK1 Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D013552:Swine; D000077602:Tolvaptan; D014162:Transfection; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002316:Cardiotonic Agents; D006727:Hormone Antagonists; D000077602:Tolvaptan; D004077:Digoxin