title: Evaluation of in vivo P-glycoprotein function at the blood-brain barrier among MDR1 gene polymorphisms by using 11C-verapamil.
abstract: P-glycoprotein (P-gp) is a membrane protein that functions as an adenosine triphosphate-dependent efflux pump for xenobiotics at the blood-brain barrier (BBB). Polymorphisms of MDR1 gene have been reported to be associated with the expression level of P-gp. (11)C-Verapamil is considered to be one of the suitable radioligands for evaluating P-gp functions. However, the metabolites of verapamil might complicate the quantitative analysis because of their possible brain penetration. In the present study, we investigated the P-gp functional differences at the BBB between the haplotypes (1236TT, 2677TT, 3435TT vs. 1236CC, 2677GG, 3435CC) of the MDR1 gene with different quantitative analyses of (11)C-verapamil.
  
  
  METHODS
  Thirty-three healthy male volunteers were enrolled in this study after identification of the haplotypes of the MDR1 gene. Brain PET scans with (11)C-verapamil were performed for 16 min. Integration plot analysis, which yields brain uptake clearance, was performed with the first 3-min data. Integration plot analysis was then compared with several other quantitative analyses with 16-min data (1-input, 1-tissue compartment model, and the area under the curve ratio (AUC(ratio)) between brain and plasma).
  
  
  RESULTS
  In the integration plot, there was no difference in the absolute values of brain uptake clearance (CL(uptake)) between the haplotypes; CL(uptake) of (11)C-verapamil for the haplotypes (1236TT, 2677TT, 3435TT vs. 1236CC, 2677GG, 3435CC) were 0.053 +/- 0.011 and 0.051 +/- 0.011 mL/g/min, respectively. CL(uptake) of (11)C-verapamil in the integration plot was significantly correlated with K1 and DV(K1/k2) (DV is distribution volume; K1 and k2 are plasma and tissue rate constants) in the 1-input, 1-tissue compartment model and the AUC(ratio).
  
  
  CONCLUSIONS
  On the basis of the several quantitative analyses of (11)C-verapamil, the assumption that the function of P-gp at the BBB is different between the haplotypes (3 single nucleotide polymorphisms: C1236T, G2677T, and C3435T) of MDR1 gene was not supported.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Takuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ikoma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D016037:Single-Blind Method; D013223:Statistics as Topic; D014018:Tissue Distribution; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil