title: Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations.
abstract: BACKGROUND
  Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.
  
  
  METHODS
  The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.
  
  
  RESULTS
  All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.
  
  
  CONCLUSIONS
  These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: R H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.affiliation: 1] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA [2] Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D000077143:Docetaxel; D004347:Drug Interactions; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077157:Sorafenib; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C503999:SLCO1B1 protein, human; C498887:Slco1b2 protein, mouse; D043823:Taxoids; D000077143:Docetaxel; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases