Brain Accumulation of Ponatinib and Its Active Metabolite, N-Desmethyl Ponatinib, Is Limited by P-Glycoprotein (P-GP/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2).
Anita KortStéphanie van HoppeRolf W SparidansEls WagenaarJos H BeijnenAlfred H SchinkelPublished in: Molecular pharmaceutics (2017)
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 in vitro 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 N-desmethyl metabolite (DMP). In vitro, 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.
Keyphrases
- chronic myeloid leukemia
- blood brain barrier
- cerebral ischemia
- resting state
- acute lymphoblastic leukemia
- white matter
- endothelial cells
- stem cells
- emergency department
- tyrosine kinase
- poor prognosis
- cancer stem cells
- high throughput
- drug resistant
- mass spectrometry
- young adults
- replacement therapy
- bone marrow
- acute myeloid leukemia
- adipose tissue
- brain injury
- binding protein
- dna methylation
- functional connectivity
- multidrug resistant
- cell therapy
- electronic health record
- single cell
- signaling pathway