Document Detail

Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.
MedLine Citation:
PMID:  15100174     Owner:  NLM     Status:  MEDLINE    
We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine.
Naoki Ishiguro; Takashi Nozawa; Akiko Tsujihata; Asami Saito; Wataru Kishimoto; Kazutoshi Yokoyama; Takafumi Yotsumoto; Kenji Sakai; Takashi Igarashi; Ikumi Tamai
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  32     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-04-21     Completed Date:  2004-12-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  519-24     Citation Subset:  IM    
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 Japan.
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MeSH Terms
Biological Transport / physiology
Blood-Brain Barrier / metabolism*
Cell Line, Transformed
Dibenzazepines / chemistry,  metabolism*
Dose-Response Relationship, Drug
Endothelium, Vascular / metabolism
Histamine H1 Antagonists / chemistry,  metabolism*
Imidazoles / chemistry,  metabolism*
LLC-PK1 Cells
Mice, Knockout
Receptors, Histamine H1 / metabolism*
Reg. No./Substance:
0/Dibenzazepines; 0/Histamine H1 Antagonists; 0/Imidazoles; 0/Receptors, Histamine H1; 80012-43-7/epinastine

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