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Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans
Author(s) -
Brunner Martin,
Langer Oliver,
SunderPlassmann Raute,
Dobrozemsky Georg,
Müller Ulrich,
Wadsak Wolfgang,
Krcal Andreas,
Karch Rudolf,
Mannhalter Christine,
Dudczak Robert,
Kletter Kurt,
Steiner Ilka,
Baumgartner Christoph,
Müller Markus
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.04.011
Subject(s) - verapamil , haplotype , p glycoprotein , pharmacokinetics , pharmacology , medicine , blood sampling , venous blood , confidence interval , endocrinology , biology , allele , gene , drug resistance , multiple drug resistance , calcium , biochemistry , genetics
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 [ 11 C]verapamil could be detected in healthy volunteers differing in ABCB1 haplotypes. Clinical Pharmacology & Therapeutics (2005) 78 , 182–190; doi: 10.1016/j.clpt.2005.04.011