Evaluation of in vivo P-glycoprotein function at the blood-brain barrier among MDR1 gene polymorphisms by using 11C-verapamil

Akihiro Takano, Hiroyuki Kusuhara, Tetsuya Suhara, Ichiro Ieiri, Takuya Morimoto, Young Joo Lee, Jun Maeda, Yoko Ikoma, Hiroshi Ito, Kazutoshi Suzuki, Yuichi Sugiyama

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91 Citations (Scopus)


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. 11C-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 11C-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 11C-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 (AUCratio) 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; CLuptake of 11C-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. CLuptake of 11C-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 AUCratio. Conclusion: On the basis of the several quantitative analyses of 11C-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.

Original languageEnglish
Pages (from-to)1427-1433
Number of pages7
JournalJournal of Nuclear Medicine
Issue number9
Publication statusPublished - Sept 1 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging


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