Print Email Facebook Twitter Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3 Title Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3 Author Gozalpour, E. Greupink, R. Wortelboer, H.M. Bilos, A. Schreurs, M. Russel, F.G.M. Koenderink, J.B. Publication year 2014 Abstract Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na+-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of β-estradiol 17-β-d- glucuronide (E217βG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 μM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 μM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces the inhibition of NTCP but decreases the inhibition of OATP1B1 and OATP1B3. To investigate whether DLCs can be translocated, we quantified their uptake in transporter-expressing cells by LC-MS. We demonstrated that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates of OATP1B3. No transport was observed for the other compounds in any of the studied transporters. In summary, this work provides a step toward an improved understanding of the interaction of DLCs with three major hepatic uptake transporters. Ultimately, this can be of use in the development of DLCs that are less prone to transporter-mediated drug-drug interactions. © 2014 American Chemical Society. Chemicals/CAS: convallatoxin, 508-75-8; cymarin, 508-77-0; digitoxigenin, 143-62-4, 25495-72-1; digitoxin, 71-63-6; digoxigenin, 1672-46-4; digoxin, 20830-75-5, 57285-89-9; dihydroouabain, 1183-35-3; estradiol 17 glucuronide, 1806-98-0; ouabagenin, 508-52-1; ouabain, 11018-89-6, 630-60-4; peruvoside, 1182-87-2; proscillaridin, 466-06-8; strophanthidin, 66-28-4; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3 Manufacturers: Sigma, Netherlands Subject LifeMSB - Microbiology and Systems BiologyELSS - Earth, Life and Social SciencesFood and NutritionBiology PharmacologyHealthy LivingBufadienolidesCardenolidesCell transportConvallatoxinDigitalis-like compoundsDihydroouabainDrug-induced toxicityNTCPOATP1B1OATP1B3OuabageninOuabainCardiac glycosideConvallatoxinCymarinDehydroouabainDigitoxigeninDigitoxinDigoxigeninDigoxinDihydroouabainEstradiol 17 glucuronideGitoxigeninHydroxyl groupOuabageninOuabainPeruvosidePlant glycosideProscillaridinSodium bile acid cotransporterSolute carrier organic anion transporter 1B1Solute carrier organic anion transporter 1B3StrophanthidinStrophanthidolSugarTaurocholic acidUnclassified drugAnimal cellChemical structureCHO cell lineControlled studyDrug interactionDrug uptakeEmbryoHumanHuman cellIC 50Kidney cellLiquid chromatographyMass spectrometryNonhuman To reference this document use: http://resolver.tudelft.nl/uuid:d12561a9-963e-444c-8284-ecd3ef9e9df3 DOI https://doi.org/10.1021/mp400699p TNO identifier 507082 Publisher American Chemical Society ISSN 1543-8392 Source Molecular Pharmaceutics, 11 (6), 1844-1855 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.