1 Ocak 2009 Dergi makalesi Açık Erişim

Vlaming, Maria L. H.; van Esch, Anita; Pala, Zeliha; Wagenaar, Els; van de Wetering, Koen; van Tellingen, Olaf; Schinkel, Alfred H.

DataCite XML

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  <identifier identifierType="URL">https://aperta.ulakbim.gov.tr/record/42687</identifier>
  <creators>
    <creator>
      <creatorName>Vlaming, Maria L. H.</creatorName>
      <givenName>Maria L. H.</givenName>
      <familyName>Vlaming</familyName>
      <affiliation>Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>van Esch, Anita</creatorName>
      <givenName>Anita</givenName>
      <familyName>van Esch</familyName>
      <affiliation>Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>Pala, Zeliha</creatorName>
      <givenName>Zeliha</givenName>
      <familyName>Pala</familyName>
      <affiliation>Istanbul Univ, Fac Pharm, Dept Pharmacol, Istanbul, Turkey</affiliation>
    </creator>
    <creator>
      <creatorName>Wagenaar, Els</creatorName>
      <givenName>Els</givenName>
      <familyName>Wagenaar</familyName>
      <affiliation>Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>van de Wetering, Koen</creatorName>
      <givenName>Koen</givenName>
      <familyName>van de Wetering</familyName>
      <affiliation>Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>van Tellingen, Olaf</creatorName>
      <givenName>Olaf</givenName>
      <familyName>van Tellingen</familyName>
      <affiliation>Netherlands Canc Inst, Div Clin Chem, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>Schinkel, Alfred H.</creatorName>
      <givenName>Alfred H.</givenName>
      <familyName>Schinkel</familyName>
      <affiliation>Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Abcc2 (Mrp2), Abcc3 (Mrp3), And Abcg2 (Bcrp1) Are The Main Determinants For Rapid Elimination Of Methotrexate And Its Toxic Metabolite 7-Hydroxymethotrexate In Vivo</title>
  </titles>
  <publisher>Aperta</publisher>
  <publicationYear>2009</publicationYear>
  <dates>
    <date dateType="Issued">2009-01-01</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://aperta.ulakbim.gov.tr/record/42687</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1158/1535-7163.MCT-09-0668</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://www.opendefinition.org/licenses/cc-by">Creative Commons Attribution</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">The multidrug transporters ABCC2, ABCC3, and ABCG2 can eliminate potentially toxic compounds from the body and have overlapping substrate specificities. To investigate the overlapping functions of Abcc2, Abcc3, and Abcg2 in vivo, we generated and characterized Abcc3;Abcg2(-/-) and Abcc2;Abcc3;Abcg2(-/-) mice. We subsequently analyzed the relative impact of these transport proteins on the pharmacokinetics of the anticancer drug methotrexate (MTX) and its main, toxic, metabolite 7-hydroxymethotrexate (70H-MTX) after i.v. administration of MTX (50 mg/kg). Whereas in single and double knockout mice, the plasma and liver concentrations of MTX and 70H-MTX decreased rapidly after MTX administration, in the Abcc2;Abcc3;Abcg2(-/-) mice, they remained very high. One hour after administration, 67% of the IVITX dose was still present in livers of Abcc2;Abcc3;Abcg2(-/-) mice as MTX or 70H-MTX versus 7% in wild-type, showing dramatic liver accumulation of these toxic compounds when Abcc2, Abcc3, and Abcg2 were all absent. Furthermore, the urinary and fecal excretion of the nephrotoxic metabolite 70H-MTX were increased 27- and 7-fold, respectively, in Abcc2;Abcc3;Abcg2(-/-) mice. Thus, Abcc2, Abcc3, and Abcg2 together mediate the rapid elimination of MTX and 70H-MTX after i.v. administration and can to a large extent compensate for each other's absence. This may explain why it is still comparatively safe to use a toxic drug such as MTX in the clinic, as the risk of highly increased toxicity due to dysfunctioning of ABCC2, ABCC3, or ABCG2 alone is limited. Nevertheless, cotreatment with possible inhibitors of ABCC2, ABCC3, and ABCG2 should be done with utmost caution when treating patients with methotrexate. [Mol Cancer Ther 2009;(12):3350-9]</description>
  </descriptions>
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