Abstract
Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. 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 interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. 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, MK-571, or 10 μM elacridar. Coincubation 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. Coincubation 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. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving tolvaptan and metabolites.
Footnotes
- Received October 16, 2105.
- Accepted March 21, 2016.
Dr. M. Pan is an employee of Otsuka Pharmaceutical Development and Commercialization, Inc. Dr. K. R. Brouwer, Ms. K. M. Freeman, and Dr. R. L. St. Claire are employed by Qualyst Transporter Solutions, LLC. Dr. K. L. R. Brouwer is a coinventor of the sandwich-cultured hepatocyte technology for quantification of biliary excretion (B-CLEAR) and related technologies, which have been licensed exclusively to Qualyst Transporter Solutions, LLC.
Funding was provided by Otsuka Pharmaceutical Development and Commercialization, Inc., and by the National Institutes of Health National Institute of General Medical Sciences [Award no. R01GM041935 (K.L.R.B.)]. The content is solely the responsibility of the authors and does not necessarily represent the official views of Otsuka or the NIH.
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- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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