title: Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood-Brain Barrier: A PET Study on Nonhuman Primates.
abstract: The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of11C-erlotinib in nonhuman primates as a model of the human BBB.
  
  
  METHODS
  Papio anubis baboons underwent PET scans of the brain after intravenous injection of11C-erlotinib under baseline conditions (n = 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3).
  
  
  RESULTS
  Under baseline conditions,11C-erlotinib distribution to the brain (total volume of distribution [VT], 0.22 ± 0.015 mL/cm3) was markedly lower than its distribution to muscle tissue surrounding the skull (VT, 0.86 ± 0.10 mL/cm3). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in11C-erlotinib distribution to the brain (VT, 0.81 ± 0.21 mL/cm3, P < 0.01), reaching levels comparable to those in muscle tissue, without changing11C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion,11C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (VT, 0.38 ± 0.033 mL/cm3, P < 0.05), with a concomitant increase in11C-erlotinib plasma exposure.
  
  
  CONCLUSIONS
  We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of11C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France nicolas.tournier@cea.fr.
authors: Nicolas
authors: N
authors: Tournier
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Sebastien
authors: S
authors: Goutal
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Sylvain
authors: S
authors: Auvity
authors: Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Alexander
authors: A
authors: Traxl
authors: Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Severin
authors: S
authors: Mairinger
authors: Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Thomas
authors: T
authors: Wanek
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Ourkia-Badia
authors: OB
authors: Helal
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Irène
authors: I
authors: Buvat
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Michael
authors: M
authors: Soussan
authors: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors: Fabien
authors: F
authors: Caillé
authors: Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.|Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; and.|Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
authors: Oliver
authors: O
authors: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D048530:Papio anubis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000166:Acridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D044005:Tetrahydroisoquinolines; D000069347:Erlotinib Hydrochloride; C083501:Elacridar
keywords: P-glycoprotein; blood–brain barrier; brain metastasis; breast cancer resistance protein; erlotinib