Toornvliet Rolf, van Berckel Bart N M, Luurtsema Gert, Lubberink Mark, Geldof Albert A, Bosch Tessa M, Oerlemans Ruud, Lammertsma Adriaan A, Franssen Eric J F
Department of Clinical Pharmacology and Pharmacy, VU University Medical Centre, Amsterdam, The Netherlands.
Clin Pharmacol Ther. 2006 Jun;79(6):540-8. doi: 10.1016/j.clpt.2006.02.004.
P-glycoprotein (P-gp) is an efflux transporter responsible for the transport of various drugs across the blood-brain barrier (BBB). Loss of P-gp function with age may be one factor in the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P-gp function. Furthermore, the relationship between BBB P-gp activity and peripheral P-gp activity in CD3-positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11-labeled (R)-verapamil was evaluated.
(R)-[(11)C]verapamil and positron emission tomography were used to assess gray matter P-gp function. Because (R)-[(11)C]verapamil is a substrate for P-gp, the volume of distribution of (R)-[(11)C]verapamil in the brain inversely reflects P-gp function in the BBB.
Mean volume of distribution values for 5 young healthy volunteers (age range, 21-27 years) and 5 elderly healthy volunteers (age range, 59-68 years) were 0.62+/-0.10 and 0.73+/-0.07, respectively (P=.03). The activity index of P-gp activity in CD3-positive leukocytes was 2.88+/-0.77 in young volunteers and 1.76+/-0.58 in elderly volunteers (P=.02).
This study showed decreased P-gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.
P-糖蛋白（P-gp）是一种外排转运蛋白，负责多种药物穿过血脑屏障（BBB）。随着年龄增长，P-糖蛋白功能丧失可能是神经退行性疾病发生和发展的一个因素。本研究的目的是评估衰老对血脑屏障P-糖蛋白功能的影响。此外，还研究了血脑屏障P-糖蛋白活性与CD3阳性白细胞中外周P-糖蛋白活性之间的关系。最后，评估了碳11标记的（R）-维拉帕米的血浆药代动力学。
使用（R）-[（11）C]维拉帕米和正电子发射断层扫描来评估灰质P-糖蛋白功能。由于（R）-[（11）C]维拉帕米是P-糖蛋白的底物，（R）-[（11）C]维拉帕米在脑中的分布容积与血脑屏障中P-糖蛋白功能呈负相关。
5名年轻健康志愿者（年龄范围21 - 27岁）和5名老年健康志愿者（年龄范围59 - 68岁）的平均分布容积值分别为0.62±0.10和0.73±0.07（P = 0.03）。年轻志愿者中CD3阳性白细胞的P-糖蛋白活性指数为2.88±0.77，老年志愿者中为1.76±0.58（P = 0.02）。
本研究表明衰老过程中P-糖蛋白活性降低。因此，老年受试者的大脑可能会接触到更高水平的药物和毒素。
