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
  • 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.
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