title: Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide.
abstract: The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used (11)C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain.
  
  
  METHODS
  (11)C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. (11)C-metoclopramide brain kinetics were compared using PET in rats (n = 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The (11)C-metoclopramide brain distribution (VT based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis.
  
  
  RESULTS
  (11)C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline (11)C-metoclopramide brain kinetics (VT = 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm(-3) using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose (11)C-metoclopramide VT (7.80 ± 1.43 mL⋅cm(-3)) with a 4.4-fold increase in K1 (influx rate constant) and a 2.3-fold increase in binding potential (k3/k4) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (VT = 6.28 ± 0.48 mL⋅cm(-3)) with a 2.0-fold increase in K1 and a 2.2-fold decrease in k2 (efflux rate), with no significant impact on binding potential. In this situation, only parent (11)C-metoclopramide could be detected in the brains of P-gp-inhibited rats.
  
  
  CONCLUSIONS
  (11)C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Pottier
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Marie
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Goutal
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Auvity
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Peyronneau
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Stute
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Buvat
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Caillé
authors.affiliation: Inserm/CEA/Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France; and CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France nicolas.tournier@cea.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D045744:Cell Line, Tumor; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008787:Metoclopramide / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D018492:Dopamine Antagonists; D011804:Quinolines; C095122:multidrug resistance protein 3; C402343:tariquidar; D008787:Metoclopramide
keywords: 11C-metoclopramide; ABC transporter; blood-brain barrier; breast cancer resistance protein; microdose