Print Email Facebook Twitter Generation of Bayesian prediction models for OATP-mediated drug-drug interactions based on inhibition screen of OATP1B1, OATP1B1∗15 and OATP1B3 Title Generation of Bayesian prediction models for OATP-mediated drug-drug interactions based on inhibition screen of OATP1B1, OATP1B1∗15 and OATP1B3 Author van de Steeg, E. Venhorst, J. Jansen, H.T. Nooijen, I.H.G. Degroot, J. Wortelboer, H.M. Vlaming, M.L.H. Publication year 2015 Abstract Human organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3 are important hepatic uptake transporters. Early assessment of OATP1B1/1B3-mediated drug-drug interactions (DDIs) is therefore important for successful drug development. A promising approach for early screening and prediction of DDIs is computational modeling. In this study we aimed to generate a rapid, single Bayesian prediction model for OATP1B1, OATP1B1∗15 and OATP1B3 inhibition. Besides our previously generated HEK-OATP1B1 and HEK-OATP1B1∗15 cells, we now generated and characterized HEK-OATP1B3 cells. Using these cell lines we investigated the inhibitory potential of 640 FDA-approved drugs from a commercial library (10 μM) on the uptake of [3H]-estradiol-17β-d-glucuronide (1 μM) by OATP1B1, OATP1B1∗15, and OATP1B3. Using a cut-off of ≥60% inhibition, 8% and 7% of the 640 drugs were potent OATP1B1 and OATP1B1∗15 inhibitors, respectively. Only 1% of the tested drugs significantly inhibited OATP1B3, which was not sufficient for Bayesian modeling. Modeling of OATP1B1 and OATP1B1∗15 inhibition revealed that presence of conjugated systems and (hetero)cycles with acceptor/donor atoms in- or outside the ring enhance the probability of a molecule binding these transporters. The overall performance of the model for OATP1B1 and OATP1B1∗15 was ≥80%, including evaluation with a true external test set. Our Bayesian classification model thus represents a fast, inexpensive and robust means of assessing potential binding of new chemical entities to OATP1B1 and OATP1B1∗15. As such, this model may be used to rank compounds early in the drug development process, helping to avoid adverse effects in a later stage due to inhibition of OATP1B1 and/or OATP1B1∗15. Chemicals/CAS: abamectin, 71751-41-2; acemetacin, 53164-05-9; atazanavir, 198904-31-3; bromocriptine mesilate, 22260-51-1; clarithromycin, 81103-11-9; clobetasol propionate, 25122-46-7; dihydroergocristine methanesulfonate, 24730-10-7; dipyridamole, 58-32-2; docetaxel, 114977-28-5; estradiol, 50-28-2; fluindostatin, 93957-54-1; fosinopril, 88889-14-9, 98048-97-6; losartan, 114798-26-4; mifepristone, 84371-65-3; nicardipine, 54527-84-3, 55985-32-5; olmesartan, 144689-63-4; pranlukast, 103177-37-3; pyrantel embonate, 22204-24-6; rapamycin, 53123-88-9; rifampicin, 13292-46-1; rifamycin, 6998-60-3, 14897-39-3, 15105-92-7; salazosulfapyridine, 599-79-1; suramin, 129-46-4, 145-63-1; telmisartan, 144701-48-4; tibolone, 5630-53-5; troglitazone, 97322-87-7 Subject LifeMSB - Microbiology and Systems Biology RAPID - Risk Analysis for Products in DevelopmentELSS - Earth, Life and Social SciencesBiomedical InnovationBiologyHealthy LivingBayesian prediction modelComputational modelingDrugdrug interactionOATPPolymorphismsTransporterAbamectinAcemetacinAtazanavirBromocriptine mesilateClarithromycinClobetasol propionateDihydroergocristine methanesulfonateDipyridamoleDocetaxelEstradiolFluindostatinFosinoprilLosartanMifepristoneNicardipineOlmesartanPranlukastPyrantel embonateRapamycinRifampicinRifamycinSalazosulfapyridineSolute carrier organic anion transporter 1B1Solute carrier organic anion transporter 1B1 15Solute carrier organic anion transporter 1B3SuraminTelmisartanTiboloneTroglitazoneUnclassified drugUnindexed drugBayesian learningControlled studyDrug protein bindingHEK293 cell lineHuman cellNucleotide sequencePredictionPriority journalProtein expressionTandem mass spectrometryUltra performance liquid chromatography To reference this document use: http://resolver.tudelft.nl/uuid:e2934f75-c46b-4c11-9bf9-bc07ed72a8dc DOI https://doi.org/10.1016/j.ejps.2015.01.004 TNO identifier 523191 ISSN 0928-0987 Source European Journal of Pharmaceutical Sciences, 70, 29-36 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.