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.
journal_name
Biopharm Drug Disposjournal_title
Biopharmaceutics & drug dispositionauthors
Hénin E,Honorat M,Guitton J,Di Pietro A,Payen L,Tod Mdoi
10.1002/bdd.2069subject
Has Abstractpub_date
2017-07-01 00:00:00pages
351-362issue
5eissn
0142-2782issn
1099-081Xjournal_volume
38pub_type
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