title: Effect of P-glycoprotein on intestinal absorption and brain penetration of antiallergic agent bepotastine besilate.
abstract: 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. [(14)C]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 K(m) 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 [(14)C]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 [(14)C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [(14)C]bepotastine disappeared. The concentration dependence of ka of [(14)C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 microM). 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.
authors.affiliation: Exploratory DMPK, Exploratory Toxicology and DMPK Research Laboratories, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, 335-8505, Japan. r-ohashi@tanabe.co.jp
authors.forename: Rikiya
authors.initials: R
authors.lastname: Ohashi
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kamikozawa
authors.forename: Mika
authors.initials: M
authors.lastname: Sugiura
authors.forename: Hajime
authors.initials: H
authors.lastname: Fukuda
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yabuuchi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001345:Autoradiography; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D002853:Chromatography, Liquid; D007408:Intestinal Absorption / Q000187:drug effects*; D007700:Kinetics; D018374:LLC-PK1 Cells; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D013552:Swine; D016593:Terfenadine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018926:Anti-Allergic Agents; D010880:Piperidines; D011725:Pyridines; C511534:bepotastine besilate; D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine; D000251:Adenosine Triphosphatases