TY - JOUR
T1 - Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[11C]verapamil and positron emission tomography
AU - Toornvliet, Rolf
AU - van Berckel, Bart N.M.
AU - Luurtsema, Gert
AU - Lubberink, Mark
AU - Geldof, Albert A.
AU - Bosch, Tessa M.
AU - Oerlemans, Ruud
AU - Lammertsma, Adriaan A.
AU - Franssen, Eric J.F.
PY - 2006/6/1
Y1 - 2006/6/1
N2 - Introduction: 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. Methods: (R)-[11C]verapamil and positron emission tomography were used to assess gray matter P-gp function. Because (R)-[11C]verapamil is a substrate for P-gp, the volume of distribution of (R)-[11C]verapamil in the brain inversely reflects P-gp function in the BBB. Results: 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). Conclusion: This study showed decreased P-gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.
AB - Introduction: 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. Methods: (R)-[11C]verapamil and positron emission tomography were used to assess gray matter P-gp function. Because (R)-[11C]verapamil is a substrate for P-gp, the volume of distribution of (R)-[11C]verapamil in the brain inversely reflects P-gp function in the BBB. Results: 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). Conclusion: This study showed decreased P-gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.
UR - http://www.scopus.com/inward/record.url?scp=33744936006&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.clpt.2006.02.004
DO - https://doi.org/10.1016/j.clpt.2006.02.004
M3 - Article
C2 - 16765142
SN - 0009-9236
VL - 79
SP - 540
EP - 548
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 6
ER -