Linked Life Data

10206323

Source:http://linkedlifedata.com/resource/pubmed/id/10206323

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1999-6-2
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0142-2782
pubmed:author
pubmed:issnType
Print
pubmed:volume
20
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
85-90
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10206323-Adrenergic beta-Antagonists, pubmed-meshheading:10206323-Animals, pubmed-meshheading:10206323-Antineoplastic Agents, Phytogenic, pubmed-meshheading:10206323-Biological Transport, Active, pubmed-meshheading:10206323-Blood-Brain Barrier, pubmed-meshheading:10206323-Brain, pubmed-meshheading:10206323-Calcium Channel Blockers, pubmed-meshheading:10206323-Cells, Cultured, pubmed-meshheading:10206323-Cyclosporine, pubmed-meshheading:10206323-Enzyme Inhibitors, pubmed-meshheading:10206323-Humans, pubmed-meshheading:10206323-KB Cells, pubmed-meshheading:10206323-Kinetics, pubmed-meshheading:10206323-L Cells (Cell Line), pubmed-meshheading:10206323-Mice, pubmed-meshheading:10206323-P-Glycoprotein, pubmed-meshheading:10206323-Propanolamines, pubmed-meshheading:10206323-Tritium, pubmed-meshheading:10206323-Verapamil, pubmed-meshheading:10206323-Vinblastine
pubmed:year
1999
pubmed:articleTitle
Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier.
pubmed:affiliation
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't