药物转运蛋白基因ABCB1中的功能单倍型对人体中枢神经系统药物分布的影响。

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

作者信息

Brunner Martin, Langer Oliver, Sunder-Plassmann Raute, Dobrozemsky Georg, Müller Ulrich, Wadsak Wolfgang, Krcal Andreas, Karch Rudolf, Mannhalter Christine, Dudczak Robert, Kletter Kurt, Steiner Ilka, Baumgartner Christoph, Müller Markus

机构信息

Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Institute of Medical and Chemical Laboratory Diagnostics, Vienna, Austria.

出版信息

Clin Pharmacol Ther. 2005 Aug;78(2):182-90. doi: 10.1016/j.clpt.2005.04.011.

DOI:10.1016/j.clpt.2005.04.011

PMID:16084852

Abstract

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.

摘要

背景与目的

据报道，人类多药耐药基因ABCB1中的单核苷酸多态性与血脑屏障处表达的外排转运蛋白P-糖蛋白的表达和功能改变有关。为了测试某些ABCB1单倍型是否导致中枢神经系统药物分布的个体差异，通过正电子发射断层扫描（PET）在两组健康志愿者中测量了模型P-糖蛋白底物钙通道阻滞剂维拉帕米的脑分布。

方法

给10名TTT单倍型（3435T、1236T和2677T）的纯合携带者（病例组）和10名野生型CGC单倍型（3435C、2677G和1236C）的纯合对照组平均静脉推注412±114MBq碳-11标记的维拉帕米，其中未标记的维拉帕米含量少于15nmol。给药后1小时进行脑组织PET成像和静脉血采样。

结果

作为脑渗透的指标，根据时间-放射性曲线计算PET时间-放射性曲线下面积（AUC）与血浆AUC的比值，病例组的平均比值为1.1±0.3（标准差）（95%置信区间，0.9-1.3），对照组为1.1±0.2（95%置信区间，0.9-1.2）（P = 0.96）。TTT和CGC单倍型的平均脑AUC值分别为31.2±3.9和35.7±5.7（P = 0.11）。血浆AUC无显著差异。