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Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interaction (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by LC-MS/MS. Pioglitazone, verapamil, MK-571 and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by tolvaptan and metabolites. Cellular accumulation of tolvaptan (0.15-50 μM), DM-4103 and DM-4107 in SCHH was concentration dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil or MK-571, or 10 μM elacridar. Co-incubation of tolvaptan with pioglitazone, verapamil, MK-571 and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5 and 23.0%, respectively, relative to control. Co-incubation with increasing tolvaptan concentrations (0.15-50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased and the BEI of digoxin decreased from 23.9% to 8.1% in the presence of 15 μM tolvaptan, consistent with inhibition of P-glycoprotein (P-gp). In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites.

Applied In Vitro ToxicologyVol. 2, No. 1 Roundtable DiscussionThe Importance of In Vitro Liver Models: Experts Discuss Whole-Cell Systems, Transporter Function, and the Best Models for Future In Vitro TestingModerator: Kenneth R. Brouwer, Participants: Stephen S. Ferguson, Yurong Lai, Gang Luo, Amy L. Roe, Donna A. Volpe, and Kyunghee YangModerator: Kenneth R. BrouwerChief Scientific Officer, Qualyst Transporter Solutions Inc., Durham, North Carolina.Search for more papers by this author, Participants: Stephen S. FergusonChemist, Molecular Toxicology and Informatics Group, NIH/NIEHS, Durham, North Carolina.Search for more papers by this author, Yurong LaiSenior Principal Scientist, Pharmaceutical Candidate Optimization Department, Bristol-Myers Squibb, New York City, New York.Search for more papers by this author, Gang LuoLead Study Director, Covance Laboratories, Madison, Wisconsin.Search for more papers by this author, Amy L. RoeProduct Safety & Regulatory Affairs, The Procter & Gamble Company, Cincinnati, Ohio.Search for more papers by this author, Donna A. VolpeDivision of Applied Regulatory Science, Food & Drug Administration, Silver Spring, Maryland.*The findings, conclusions, and opinions expressed in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.Search for more papers by this author, and Kyunghee YangScientist, DILIsym Services Inc., Research Triangle Park, North Carolina.Search for more papers by this authorPublished Online:14 Mar 2016https://doi.org/10.1089/aivt.2016.29004.rtlAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byCharacterisation of a functional rat hepatocyte spheroid modelToxicology in Vitro, Vol. 55The C-DILI™ Assay: An Integrated In Vitro Approach to Predict Cholestatic Hepatotoxicity24 April 2019Impact of cell types and culture methods on the functionality of in vitro liver systems – A review of cell systems for hepatotoxicity assessmentToxicology in Vitro, Vol. 48Translating New Science Into the Drug Review Process: The US FDA’s Division of Applied Regulatory Science30 December 2018 | Therapeutic Innovation & Regulatory Science, Vol. 52, No. 2 Volume 2Issue 1Mar 2016 InformationCopyright 2016, Mary Ann Liebert, Inc.To cite this article:Moderator:, Kenneth R. Brouwer, Participants:, Stephen S. Ferguson, Yurong Lai, Gang Luo, Amy L. Roe, Donna A. Volpe, and Kyunghee Yang.The Importance of In Vitro Liver Models: Experts Discuss Whole-Cell Systems, Transporter Function, and the Best Models for Future In Vitro Testing.Applied In Vitro Toxicology.Mar 2016.1-7.http://doi.org/10.1089/aivt.2016.29004.rtlPublished in Volume: 2 Issue 1: March 14, 2016PDF download