RRC ID 61485
Author Matsuzaki J, Yamamoto C, Miyama T, Takanaga H, Matsuo H, Ishizuka H, Kawahara Y, Kuwano M, Naito M, Tsuruo T, Sawada Y.
Title Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier.
Journal Biopharm Drug Dispos
Abstract In this study, we investigated the mechanism of the blood-brain barrier (BBB) transport of bunitrolol (BTL), as a model of beta-blocker, in vivo and in vitro. In order to define the contribution of P-glycoprotein (P-gp) to the active efflux of BTL from brain to blood, we examined the in vivo brain distribution of BTL in mdr1a(-/-) mice with a disrupted mdr1a gene. After intravenous administration of BTL to mdr1a(-/-) mice, the brain concentration and Kp value of BTL were significantly increased as compared with those in mdr1a(+/+) mice. Next, the contribution of the mdr1a P-gp to in vitro uptake of BTL was compared in LV500 cells and L cells (mouse mdr1a-expressing cells and host cells, respectively). The intracellular accumulations of [3H]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P-gp inhibitor. Furthermore, the BTL uptake by KB-VJ300 cells, which express human P-gp, was also significantly lower than that by KB host cells, and was increased by verapamil. The steady-state uptake of BTL by LLC-GA5-COL300 cells, expressing human P-gp, was significantly increased in the presence of 20 microM cyclosporin A (another P-gp inhibitor), which had no effect in the LLC-PK1 host cells. On the other hand, the steady-state intracellular accumulation of BTL by MBEC4 cells, which express mdr1b P-gp instead of mdr1a P-gp, was not significantly changed in the presence of verapamil. This finding suggested that BTL is not a good substrate for mdr1b P-gp. In conclusion, our results suggest that BTL is transported from brain to blood by mdr1a P-gp in mice and by MDR1 in humans, and this presumably accounts for the low brain distribution of BTL.
Volume 20(2)
Pages 85-90
Published 1999-3-1
DOI 10.1002/(sici)1099-081x(199903)20:2<85::aid-bdd159>3.0.co;2-3
PII 10.1002/(SICI)1099-081X(199903)20:2<85::AID-BDD159>3.0.CO;2-3
PMID 10206323
MeSH ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology* Adrenergic beta-Antagonists / blood Adrenergic beta-Antagonists / pharmacokinetics* Animals Antineoplastic Agents, Phytogenic / pharmacokinetics Biological Transport, Active / drug effects Blood-Brain Barrier / drug effects Blood-Brain Barrier / physiology* Brain / metabolism Calcium Channel Blockers / pharmacology Cells, Cultured Cyclosporine / pharmacology Enzyme Inhibitors / pharmacology Humans KB Cells Kinetics L Cells Mice Propanolamines / blood Propanolamines / pharmacokinetics* Tritium Verapamil / pharmacology Vinblastine / pharmacokinetics
IF 1.663
Human and Animal Cells LLC-GA5-CoL300(RCB0872)