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).

Abstract	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.
Authors	Anita Kort, Stéphanie van Hoppe, Rolf W Sparidans, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
Journal	Molecular pharmaceutics (Mol Pharm) Vol. 14 Issue 10 Pg. 3258-3268 (10 02 2017) ISSN: 1543-8392 [Electronic] United States
PMID	28880088 (Publication Type: Journal Article)
Chemical References	ABCB1 protein, human ABCG2 protein, human ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily G, Member 2 Abcg2 protein, mouse Antineoplastic Agents Imidazoles Neoplasm Proteins Protein Kinase Inhibitors Pyridazines ponatinib Cytochrome P-450 Enzyme System multidrug resistance protein 3 CYP3A protein, mouse Cytochrome P-450 CYP3A Fusion Proteins, bcr-abl
Topics	ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, genetics, metabolism) ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors, genetics, metabolism) Animals Antineoplastic Agents (pharmacology) Biological Availability Biological Transport (drug effects) Blood-Brain Barrier (drug effects) Brain (metabolism) Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System (genetics, metabolism) Dogs Female Fusion Proteins, bcr-abl (antagonists & inhibitors) Humans Imidazoles (pharmacology) Madin Darby Canine Kidney Cells Mice Mice, Knockout Neoplasm Proteins (antagonists & inhibitors, metabolism) Protein Kinase Inhibitors (pharmacology) Pyridazines (pharmacology) Tissue Distribution

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