title: Pharmacokinetic interactions in mice between irinotecan and MBL-II-141, an ABCG2 inhibitor.
abstract: OBJECTIVE
  The chromone derivative MBL-II-141, specifically designed to inhibit ABCG2, was previously demonstrated to combine strong inhibition potency, low toxicity and good efficiency in reversing resistance to irinotecan in a xenografted mouse model. Here, the pharmacokinetic interactions in mice between irinotecan, its active metabolite SN-38 and MBL-II-141 were characterized quantitatively in the blood and in the brain.
  
  
  METHODS
  Compartmental models were used to fit the data. Goodness-of-fit was assessed by simulation-based diagnostic tools.
  
  
  RESULTS
  Irinotecan increased the MBL-II-141 apparent clearance and Vss 1.5-fold, probably by increasing the MBL-II-141 unbound fraction. MBL-II-141 decreased the total apparent clearance of irinotecan by 23%, by decreasing its biliary clearance. MBL-II-141 increased 3-fold the brain accumulation of irinotecan, as a result of the rise of systemic exposure combined with the inhibition of ABCG2-mediated efflux at the blood-brain barrier. Finally, SN-38 exposure was increased by 1.16-fold under treatment with MBL-II-141, owing to the higher irinotecan exposure with increased metabolism towards the formation of SN-38.
  
  
  CONCLUSIONS
  These results may help to anticipate the pharmacokinetic interactions between MBL-II-141 and other ABCG2 substrates. The irinotecan-MBL-II-141 interaction is also expected to occur in humans. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Université de Lyon, F-69373, Lyon, France.|Université Lyon 1, EMR3738, Faculté de médecine Lyon-sud, Pierre Bénite, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.affiliation: Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69000, France.|Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de pharmacologie-toxicologie, F-69495, Pierre Bénite, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Honorat
authors.affiliation: Université de Lyon, F-69373, Lyon, France.|Université Lyon 1, EMR3738, Faculté de médecine Lyon-sud, Pierre Bénite, France.|Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de pharmacologie-toxicologie, F-69495, Pierre Bénite, France.|Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.affiliation: Institut de Biologie et Chimie des Protéines F-69367, MMSB, UMR5086 CNRS-Université Lyon 1, Lyon, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Université de Lyon, F-69373, Lyon, France.|Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69000, France.|Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, Lyon, France.|Centre Hospitalier Lyon-Sud, Laboratoire de biologie, Hospices Civils de Lyon, F-69495, Pierre Bénite, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Payen
authors.affiliation: Université de Lyon, F-69373, Lyon, France.|Université Lyon 1, EMR3738, Faculté de médecine Lyon-sud, Pierre Bénite, France.|Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, Lyon, France.|Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Pharmacie, F-69004, Lyon, France.
authors.forename: Michel
authors.identifier: http://orcid.org/0000-0002-4632-5586
authors.initials: M
authors.lastname: Tod
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002867:Chromones / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D000077146:Irinotecan; D016513:Mice, SCID; D008954:Models, Biological
chemical_list: C571193:5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D007211:Indoles; D000077146:Irinotecan; D002166:Camptothecin
keywords: ABCG2; brain accumulation; inhibition; irinotecan; pharmacokinetics