Details

Autor(en) / Beteiligte

• Hénin, Emilie
• Honorat, Mylène
• Guitton, Jérôme
• Di Pietro, Attilio
• Payen, Léa
• Tod, Michel

Titel

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

Ist Teil von

• Biopharmaceutics & drug disposition, 2017-07, Vol.38 (5), p.351-362

Ort / Verlag

England: Wiley Subscription Services, Inc

Erscheinungsjahr

2017

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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.