title: Influence of human OATP1B1, OATP1B3, and OATP1A2 on the pharmacokinetics of methotrexate and paclitaxel in humanized transgenic mice.
abstract: OBJECTIVE
  Organic anion-transporting polypeptide (OATP) drug uptake transporters are thought to play an important role in drug pharmacokinetics and toxicokinetics. We aimed to determine the influence of the individual human OATP1B1, OATP1B3, and OATP1A2 transporters on the in vivo disposition of the anticancer drugs methotrexate and paclitaxel by using liver-specific humanized OATP1A/1B transgenic mice.
  
  
  METHODS
  Wild-type, Slco1a/1b(-/-) (Oatp1a/1b knockout), Slco1a/1b(-/-);1B1(tg), Slco1a/1b(-/-);1B3(tg), and newly generated Slco1a/1b(-/-);1A2(tg) (humanized OATP1B1, OATP1B3, and OATP1A2 transgenic) mice were characterized biochemically and physiologically, and subsequently intravenously dosed with methotrexate or paclitaxel (2 or 10 mg/kg each) for pharmacokinetic analyses.
  
  
  RESULTS
  Humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice all showed partial or complete rescue of increased plasma bilirubin levels, but also of the increased plasma levels and decreased liver and small intestinal accumulation of methotrexate observed in Slco1a/1b(-/-) mice. Furthermore, hepatic expression of OATP1B3 and OATP1A2, but not OATP1B1, resulted in increased liver uptake of paclitaxel (2 mg/kg). At 10 mg/kg, a modest effect of only OATP1A2 on paclitaxel liver uptake was observed.
  
  
  CONCLUSIONS
  Human OATP1A/1B transporters play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutics methotrexate (organic anion) and paclitaxel (hydrophobic, bulky). Variation in OATP1A/1B activity due to genetic variation and pharmacologic inhibition, or differences in tumor-specific expression levels might therefore affect plasma, tissue, and tumor levels of these drugs in patients, and hence their therapeutic efficacy. Humanized transgenic OATP1A/1B mice will provide excellent tools to further study these aspects in vivo for many (anticancer) drugs.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Evita
authors.initials: E
authors.lastname: van de Steeg
authors.forename: Anita
authors.initials: A
authors.lastname: van Esch
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Kenworthy
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood; D006801:Humans; D008099:Liver / Q000187:drug effects; D027381:Liver-Specific Organic Anion Transporter 1; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014018:Tissue Distribution
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C512988:SLCO1A2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D017239:Paclitaxel; D001663:Bilirubin; D008727:Methotrexate