title: Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues.
abstract: OBJECTIVE
  Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacologic relevance of ABCC4 at the BBB is difficult to evaluate, as most drugs are also substrates of ABCB1 and/or ABCG2.
  
  
  METHODS
  We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogues, an important class of antineoplastic agents and substrates of these transporters. Wild-type (WT), Abcg2(-/-), Abcb1a/b(-/-), Abcc4(-/-), Abcb1a/b;Abcg2(-/-), Abcg2;Abcc4(-/-), and Abcb1a/b;Abcg2;Abcc4(-/-) mice received i.v. topotecan, irinotecan, SN-38, or gimatecan alone or with concomitant oral elacridar. Drug levels were analyzed by high-performance liquid chromatography (HPLC).
  
  
  RESULTS
  We found that additional deficiency of Abcc4 in Abcb1a/b;Abcg2(-/-) mice significantly increased the brain concentration of all camptothecin analogues by 1.2-fold (gimatecan) to 5.8-fold (SN-38). The presence of Abcb1a/b or Abcc4 alone was sufficient to reduce the brain concentration of SN-38 to the level in WT mice. Strikingly, the brain distribution of gimatecan in brain of WT mice was more than 220- and 40-fold higher than that of SN-38 and topotecan, respectively.
  
  
  CONCLUSIONS
  Abcc4 limits the brain penetration of camptothecin analogues and teams up with Abcb1a/b and Abcg2 to form a robust cooperative drug efflux system. This concerted action limits the usefulness of selective ABC transport inhibitors to enhance drug entry for treatment of intracranial diseases. Our results also suggest that gimatecan might be a better candidate than irinotecan for clinical evaluation against intracranial tumors.
authors: Department of Clinical Chemistry/Preclinical Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, EC Amsterdam, The Netherlands.
authors: Fan
authors: F
authors: Lin
authors: Serena
authors: S
authors: Marchetti
authors: Dick
authors: D
authors: Pluim
authors: Dilek
authors: D
authors: Iusuf
authors: Roberto
authors: R
authors: Mazzanti
authors: Jan H M
authors: JH
authors: Schellens
authors: Jos H
authors: JH
authors: Beijnen
authors: Olaf
authors: O
authors: van Tellingen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077146:Irinotecan; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D019772:Topotecan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D044005:Tetrahydroisoquinolines; D019772:Topotecan; C489540:Abcc4 protein, mouse; C501412:Abcg2 protein, mouse; C433984:ST 1481; C083501:Elacridar