P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice.

Abstract

Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33-51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.

• Authors: Jing Wang, Changpei Gan, Irene A Retmana, Rolf W Sparidans, Wenlong Li, Maria C Lebre, Jos H Beijnen, Alfred H Schinkel
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 556 Pg. 172-180 (Feb 10 2019) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 30553002 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

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
• Benzothiazoles
• Neoplasm Proteins
• Phenylurea Compounds
• quizartinib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Benzothiazoles (administration & dosage, pharmacokinetics)
• Biological Availability
• Brain (metabolism)
• Dogs
• Female
• Humans
• Madin Darby Canine Kidney Cells
• Mice
• Mice, Knockout
• Mice, Transgenic
• Neoplasm Proteins (genetics, metabolism)
• Phenylurea Compounds (administration & dosage, pharmacokinetics)
• Tissue Distribution
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors)