1 research outputs found
Brain Accumulation of Ponatinib and Its Active Metabolite, <i>N</i>‑Desmethyl Ponatinib, Is Limited by P‑Glycoprotein (P-GP/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2)
Ponatinib is an oral BCR-ABL1 inhibitor
for treatment of advanced
leukemic diseases that carry the Philadelphia chromosome, specifically
containing the T315I mutation yielding resistance to previously approved
BCR-ABL1 inhibitors. Using <i>in vitro</i> transport assays
and knockout mouse models, we investigated whether the multidrug efflux
transporters ABCB1 and ABCG2 transport ponatinib and whether they,
or the drug-metabolizing enzyme CYP3A, affect the oral availability
and brain accumulation of ponatinib and its active <i>N</i>-desmethyl metabolite (DMP). <i>In vitro</i>, mouse Abcg2
and human ABCB1 modestly transported ponatinib. In mice, both Abcb1
and Abcg2 markedly restricted brain accumulation of ponatinib and
DMP, but not ponatinib oral availability. Abcg2 deficiency increased
DMP plasma levels ∼3-fold. Cyp3a deficiency increased the ponatinib
plasma AUC 1.4-fold. Our results suggest that pharmacological inhibition
of ABCG2 and ABCB1 during ponatinib therapy might benefit patients
with brain (micro)metastases positioned behind an intact blood-brain
barrier, or with substantial expression of these transporters in the
malignant cells. CYP3A inhibitors might increase ponatinib oral availability,
enhancing efficacy but possibly also toxicity of this drug