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Evaluation of In Vivo P-Glycoprotein Function at the Blood–Brain Barrier Among MDR1 Gene Polymorphisms by Using ¹¹C-Verapamil

¹ Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; ² Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; and ³ Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan

Correspondence: For correspondence or reprints contact: Yuichi Sugiyama, PhD, Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

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 (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 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. CL_uptake 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 AUC_ratio. 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.

Key Words: P-glycoprotein • blood–brain barrier • polymorphism • ¹¹C-verapamil • PET

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