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Pharmacokinetic interactions in mice between irinotecan and MBL‐II‐141, an ABCG2 inhibitor
Author(s) -
Hénin Emilie,
Honorat Mylène,
Guitton Jérôme,
Di Pietro Attilio,
Payen Léa,
Tod Michel
Publication year - 2017
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2069
Subject(s) - irinotecan , pharmacokinetics , pharmacology , abcg2 , chemistry , sn 38 , active metabolite , metabolite , transporter , medicine , atp binding cassette transporter , biochemistry , cancer , colorectal cancer , gene
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 V ss 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.