title: P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387.
abstract: CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Durmus
authors.forename: N
authors.initials: N
authors.lastname: Xu
authors.forename: R W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: E
authors.initials: E
authors.lastname: Wagenaar
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005260:Female; D017353:Gene Deletion; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases; D009363:Neoplasm Proteins; D011743:Pyrimidines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C501412:Abcg2 protein, mouse; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C095122:multidrug resistance protein 3
keywords: AUC; BBB; BCRP; Brain accumulation; CYT387; Cmax; JAK1/2 inhibitor; MDR1; Oral availability; P-glycoprotein; SD; Tmax; area under the plasma concentration–time curve; blood–brain barrier; breast cancer resistance protein; maximum drug concentration in plasma; multidrug resistance protein; standard deviation; the time after administration of a drug when the maximum plasma concentration is reached