title: P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib.
abstract: BACKGROUND
  Palbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor with nanomolar potency and was recently approved for treatment of breast cancer. The drug may also be useful in glioblastoma (GBM) and diffuse intrinsic pontine gliomas (DIPG), which often have an activated CDK4/6-retinoblastoma signaling pathway. However, GBM and DIPG spread widely into the surrounding brain, which calls for a CDK4/6 inhibitor with sufficient blood-brain barrier penetration.
  
  
  METHODS
  We first performed in vitro transwell assays and demonstrate that palbociclib is a substrate of both P-gp and BCRP. Next, we conducted pharmacokinetic studies using wildtype, Abcg2(-/-), Abcb1a/b(-/-) and Abcg2; Abcb1a/b(-/-) mice.
  
  
  RESULTS
  The plasma levels were about 3000 and 500 nM and similar in all genotypes at 1 and 4 h after i.v. administration of 10 mg/kg. At 4 h the brain-to-plasma ratios were 0.3 in WT and Abcg2(-/-) mice versus 5.5 and 15 in Abcb1a/b(-/-) and Abcg2; Abcb1a/b(-/-) mice, respectively. The oral bioavailability of palbociclib was high (63 %) in WT mice and increased only modestly and non-significantly in Abcg2; Abcb1a/b(-/-) mice. The plasma level after oral dosing of 150 mg/kg was already much higher than observed in patients (200-400 nM) and exceeded 2500 nM for up to 24 h. This latter dose is commonly used in preclinical studies, which calls into question their predictive value as they were conducted at dose levels causing a clinically non-relevant systemic drug exposure.
  
  
  CONCLUSIONS
  Thus, the brain penetration of palbociclib is restricted by P-gp and BCRP, which may restrict the efficacy against GBM and DIPG. Moreover, preclinical studies with this agent should be conducted at a more clinically relevant dose level.
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Mark C
authors.initials: MC
authors.lastname: de Gooijer
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Department of Neurosurgery, Qilu Hospital, Shandong University, Wenhua Xi Road 107, 250012, Jinan, People's Republic China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Nishita
authors.initials: N
authors.lastname: Thota
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Isabel
authors.initials: I
authors.lastname: Mayayo-Peralta
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Levi C M
authors.initials: LC
authors.lastname: Buil
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute /Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Division of Drug Toxicology, Faculty of Pharmacy, Division of Biomedical Analysis, Faculty of Science, Utrecht University, Sorbonnelaan 16, 3584 CA, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, AKL room C1.005, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. o.v.tellingen@nki.nl.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D005909:Glioblastoma / Q000188:drug therapy; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D010879:Piperazines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
keywords: ABC transporters; CDK4/6; Glioma; Palbociclib; Pharmacokinetics