title: Tetronic® 904-containing polymeric micelles overcome the overexpression of ABCG2 in the blood-brain barrier of rats and boost the penetration of the antiretroviral efavirenz into the CNS.
abstract: OBJECTIVE
  To assess the involvement of ABCG2 in the pharmacokinetics of efavirenz in the blood-brain barrier (BBB) and investigate a nanotechnology strategy to overcome its overexpression under a model of chronic oral administration. Materials & methods A model of chronic efavirenz (EFV) administration was established in male Sprague-Dawley rats treated with a daily oral dose over 5 days. Then, different treatments were conducted and drug concentrations in plasma and brain measured.
  
  
  RESULTS
  Chronic treatment with oral EFV led to the overexpression of ABCG2 in the BBB that was reverted after a brief washout period. Moreover, gefitinib and the polymeric amphiphile Tetronic(®) 904 significantly inhibited the activity of the pump and potentiated the accumulation of EFV in CNS. The same effect was observed when the drug was administered within mixed micelles containing TetronicT904 as the main component.
  
  
  CONCLUSIONS
  Tetronic 904-containing polymeric micelles overcame the overexpression of ABCG2 in the BBB caused by chronic administration of EFV then boosting its penetration into the CNS.
authors.affiliation: Pharmacology Research Institute, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Martín I
authors.initials: MI
authors.lastname: Roma
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Christian
authors.initials: C
authors.lastname: Hocht
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
authors.affiliation: Pharmacology Research Institute, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.|Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Stefania S
authors.initials: SS
authors.lastname: Di Gennaro
authors.affiliation: Pharmacology Research Institute, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.|Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Minoia
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Bramuglia
authors.affiliation: Pharmacology Research Institute, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.|Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Modesto C
authors.initials: MC
authors.lastname: Rubio
authors.affiliation: Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science & Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosnik
authors.affiliation: Pharmacology Research Institute, University of Buenos Aires & National Science Research Council (CONICET), Buenos Aires, Argentina.|Department of Pharmacology, Faculty of Pharmacy & Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Roxana N
authors.initials: RN
authors.lastname: Peroni
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000480:Alkynes; D000818:Animals; D048588:Benzoxazines / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D003521:Cyclopropanes; D005029:Ethylenediamines / Q000737:chemistry*; D008297:Male; D008823:Micelles; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D005029:Ethylenediamines; D008823:Micelles; D011108:Polymers; D018894:Reverse Transcriptase Inhibitors; C525597:Tetronic 904; C098320:efavirenz
keywords: ABCG2 pump inhibition; CNS; HIV; drug-loaded poly(ethylene oxide)-b-poly(propylene oxide) polymeric micelles; efavirenz