Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans

Background and Objective: Single nucleotide polymorphisms in the human multidrug-resistance gene ABCB1 have been reported to be associated with altered expression and function of P-glycoprotein, an efflux transporter, expressed at the blood-brain barrier. To test whether certain ABCB1 haplotypes contribute to interindividual differences in central nervous system drug distribution, brain distribution of a model P-glycoprotein substrate, the calcium channel inhibitor verapamil, was measured by positron emission tomography (PET) in 2 groups of healthy volunteers. Methods: Ten homozygous carriers (cases) of the TTT haplotype (3435T, 1236T, and 2677T) and 10 controls homozygous for the wild-type CGC haplotype (3435C, 2677G, and 1236C) were administered a mean intravenous bolus of 412 ± 114 MBq carbon 11-labeled verapamil containing less than 15 nmol of unlabeled verapamil. PET imaging of brain tissue and venous blood sampling were performed for 1 hour after dosing. Results: As a measure of brain penetration, the ratio of PET area under the time-radioactivity curve (AUC) to plasma AUC was calculated from time-radioactivity curves, with a mean ratio of 1.1 ± 0.3 (SD) (95% confidence interval, 0.9–1.3) for cases and 1.1 ± 0.2 (95% confidence interval, 0.9–1.2) for controls, respectively (P = .96). Mean brain AUC values were 31.2 ± 3.9 and 35.7 ± 5.7 for the TTT and CGC haplotype, respectively (P = .11). Plasma AUCs were not significantly different. Conclusion: No difference in the brain distribution of [¹¹C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes. [Copyright &y& Elsevier]