title: High impact of Oatp1a/1b transporters on in vivo disposition of the hydrophobic anticancer drug paclitaxel.
abstract: OBJECTIVE
  Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).
  
  
  METHODS
  Recently generated Slco1a/1b(-/-) (lacking all Oatp1a/1b transporters) and wild-type mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.
  
  
  RESULTS
  In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b(-/-) mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b(-/-) mice compared with wild-type. Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b(-/-) mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.
  
  
  CONCLUSIONS
  Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs.
authors.affiliation: Division of Molecular Biology, 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: Cornelia M M
authors.initials: CM
authors.lastname: van der Kruijssen
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Kenworthy
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057927:Hydrophobic and Hydrophilic Interactions; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008727:Methotrexate / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000494:pharmacology* / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000494:pharmacology*; D017239:Paclitaxel / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; C464433:Oatp2 protein, mouse; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C498887:Slco1b2 protein, mouse; D017239:Paclitaxel; D008727:Methotrexate