RT Journal Article
SR Electronic
T1 EFFECT OF P-GLYCOPROTEIN ON INTESTINAL ABSORPTION AND BRAIN PENETRATION OF ANTIALLERGIC AGENT BEPOTASTINE BESILATE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 793
OP 799
DO 10.1124/dmd.105.007559
VO 34
IS 5
A1 Rikiya Ohashi
A1 Yukari Kamikozawa
A1 Mika Sugiura
A1 Hajime Fukuda
A1 Hikaru Yabuuchi
A1 Ikumi Tamai
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/793.abstract
AB The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the pharmacokinetics of bepotastine, intestinal absorption and brain penetration studies were performed. [14C]Bepotastine transport in P-gp-overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low, with a Km value of 1.25 mM. After i.v. administration, the brain/plasma free concentration ratio in mdr1-knockout mice was 3 times higher than that in wild-type mice. The in situ intestinal absorption studies of [14C]bepotastine in rats showed a clear regional difference, showing highest permeability at the upper part of small intestine with a decreasing permeability in the descending part of small intestine. The apparent absorption rate constant (ka) of [14C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [14C]bepotastine disappeared. The concentration dependence of ka of [14C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 μM). In conclusion, bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofenadine. The American Society for Pharmacology and Experimental Therapeutics