title: Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.
abstract: OBJECTIVE
  To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420.
  
  
  METHODS
  After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers.
  
  
  RESULTS
  P(Brain) in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P(Brain) in Abcg2(-/-) and Mdr1a/b(-/-)Abcg2(-/-) mice were significantly higher than in wild-type mice. Mdr1a/b(-/-) mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells.
  
  
  CONCLUSIONS
  Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elmeliegy
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
authors.forename: Michael
authors.initials: M
authors.lastname: Tagen
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011799:Quinazolines / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; C487471:OSI-420; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride