Effect of P-glycoprotein inhibition at the blood-brain barrier on brain distribution of (R)-[11C]verapamil in elderly vs. young subjects
Effect of P-glycoprotein inhibition at the blood-brain barrier on brain distribution of (R)-[11C]verapamil in elderly vs. young subjects
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DOI：
10.1111/bcp.13301
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发表时间：
2017-09-01
影响因子：
3.4
通讯作者：
Langer, Oliver
中科院分区：
文献类型：
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作者：
Bauer, Martin;Wulkersdorfer, Beatrix;Langer, Oliver
目的外排转运蛋白P-糖蛋白(ABCB1)作用于血脑屏障，限制多种药物从血液到脑内的分布。先前的数据表明，与年龄相关的ABCB1在血脑屏障的表达和功能下降。在本研究中，我们研究了年龄对ABCB1介导的药物-药物相互作用(DDI)大小的影响。方法：我们使用ABCB1底物(R)-[C-11]维拉帕米模型对5名年轻[26+/-1岁，(平均+/-标准差)]和5名老年(68+/-6岁)健康男性志愿者在静脉注射小剂量ABCB1抑制剂(3 mg kg(-1))前后进行了正电子发射断层扫描。(R)-[C-11]维拉帕米在全脑灰质的总分布体积(VT)在老年组(VT=0.78+/-0.15)和青年组(VT=0.79+/-0.10)之间无显著差异。部分(不完全)ABCB1抑制后，老年组VT值(VT=0.040.0 8+/-0.15)显著高于青年组(VT=0.80+/-0.18)。部分抑制ABCB1后，老年患者(+40+/-17%)的(R)-[C-11]维拉帕米VT增加的百分比显著高于青年志愿者(+2+/-17%)(P=0.032)。青年组(786+/-178nmol L(-1))和老年组(1116+/-347nmol L(-1))的泰奎达血药浓度差异无统计学意义。结论首次提供了老年人血脑屏障ABCB1介导的DDIS风险增加的直接证据，这可能对老年人的药物治疗具有重要意义。
AIMSThe efflux transporter P-glycoprotein (ABCB1) acts at the blood-brain barrier (BBB) to restrict the distribution of many different drugs from blood to the brain. Previous data suggest an age-associated decrease in the expression and function of ABCB1 at the BBB. In the present study, we investigated the influence of age on the magnitude of an ABCB1-mediated drug-drug interaction (DDI) at the BBB.METHODSWe performed positron emission tomography scans using the model ABCB1 substrate (R)-[C-11] verapamil in five young [26 +/- 1 years, (mean +/- standard deviation)] and five elderly (68 +/- 6 years) healthy male volunteers before and after intravenous administration of a low dose of the ABCB1 inhibitor tariquidar (3 mg kg(-1)).RESULTSIn baseline scans, the total distribution volume (VT) of (R)-[C-11] verapamil in whole-brain grey matter was not significantly different between the elderly (VT = 0.78 +/- 0.15) and young (VT = 0.79 +/- 0.10) group. After partial (incomplete) ABCB1 inhibition, VT values were significantly higher (P = 0.040) in the elderly (VT = 1.08 +/- 0.15) than in the young (VT = 0.80 +/- 0.18) group. The percentage increase in (R)-[C-11] verapamil VT following partial ABCB1 inhibition was significantly greater (P = 0.032) in elderly (+40 +/- 17%) than in young (+2 +/- 17%) volunteers. Tariquidar plasma concentrations were not significantly different between the young (786 +/- 178 nmol l(-1)) and elderly (1116 +/- 347 nmol l(-1)) group.CONCLUSIONSOur results provide the first direct evidence of an increased risk for ABCB1-mediated DDIs at the BBB in elderly persons, which may have important consequences for pharmacotherapy of the elderly.