title: In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions.
abstract: OBJECTIVE
  To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter.
  
  
  METHODS
  The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways.
  
  
  RESULTS
  Sixty-five compounds were identified as OATP1B1 inhibitors at 20 μM. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified.
  
  
  CONCLUSIONS
  Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.
authors.affiliation: Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, The Biomedical Centre, P.O. Box 580, 751 23, Uppsala, Sweden. maria.karlgren@farmaci.uu.se
authors.forename: Maria
authors.initials: M
authors.lastname: Karlgren
authors.forename: Gustav
authors.initials: G
authors.lastname: Ahlin
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.forename: Johan
authors.initials: J
authors.lastname: Palm
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D000069059:Atorvastatin; D003198:Computer Simulation; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D000069059:Atorvastatin