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

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.