title: Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699).
abstract: BACKGROUND
  Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations in the breast cancer associated (BRCA) genes.
  
  
  OBJECTIVE
  We aimed to establish whether the multidrug efflux transporters ABCG2 (BCRP) and ABCB1 (P-gp, MDR1) affect the oral availability and brain penetration of rucaparib in mice.
  
  
  RESULTS
  In vitro, rucaparib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2. Transport could be inhibited by the small-molecule ABCB1 and ABCG2 inhibitors zosuquidar and Ko143, respectively. In vivo, oral availability (plasma AUC0-1 and AUC0-24) and brain levels of rucaparib at 1 and 24 h were increased by the absence of both Abcg2 and Abcb1a/1b after oral administration of rucaparib at 10 mg/kg.
  
  
  CONCLUSIONS
  Our data show to our knowledge for the first time that oral availability and brain accumulation of a PARP inhibitor are markedly and additively restricted by Abcg2 and Abcb1a/1b. This may have clinical relevance for improvement of rucaparib therapy in PARP inhibitor-resistant tumors with ABCB1 and/or ABCG2 expression and in patients with brain (micro)metastases positioned behind a functional blood-brain barrier.
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors: Selvi
authors: S
authors: Durmus
authors: Rolf W
authors: RW
authors: Sparidans
authors: Anita
authors: A
authors: van Esch
authors: Els
authors: E
authors: Wagenaar
authors: Jos H
authors: JH
authors: Beijnen
authors: Alfred H
authors: AH
authors: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D018929:Cell Culture Techniques; D004285:Dogs; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061985:Madin Darby Canine Kidney Cells; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D007211:Indoles; D009363:Neoplasm Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib