2. Academic Validation
  3. Pharmacokinetic interactions in mice between irinotecan and MBL-II-141, an ABCG2 inhibitor

Pharmacokinetic interactions in mice between irinotecan and MBL-II-141, an ABCG2 inhibitor

  • Biopharm Drug Dispos. 2017 Jul;38(5):351-362. doi: 10.1002/bdd.2069.
Emilie Hénin 1 2,  Mylène Honorat 3 4,  Jérôme Guitton 1 2 4 5,  Attilio Di Pietro 6,  Léa Payen 1 3 5 7,  Michel Tod 1 2 5 8
Affiliations

Affiliations

  • 1 Université de Lyon, F-69373, Lyon, France.
  • 2 Université Lyon 1, EMR3738, Faculté de médecine Lyon-sud, Pierre Bénite, France.
  • 3 Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69000, France.
  • 4 Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Laboratoire de pharmacologie-toxicologie, F-69495, Pierre Bénite, France.
  • 5 Université Lyon 1, ISPBL, Faculté de pharmacie, Laboratoire de Toxicologie, Lyon, France.
  • 6 Institut de Biologie et Chimie des Protéines F-69367, MMSB, UMR5086 CNRS-Université Lyon 1, Lyon, France.
  • 7 Centre Hospitalier Lyon-Sud, Laboratoire de biologie, Hospices Civils de Lyon, F-69495, Pierre Bénite, France.
  • 8 Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Pharmacie, F-69004, Lyon, France.
PMID: 28207160 DOI: 10.1002/bdd.2069
Abstract

Purpose: 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.

Keywords

ABCG2; brain accumulation; inhibition; irinotecan; pharmacokinetics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-17648
    ABCG2抑制剂
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