title: Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol.
abstract: Gastrointestinal absorption of several beta-blockers is inhibited by citrus juices, although molecular mechanism(s) lying on their small intestinal absorption has not yet been identified. Here, we attempted to demonstrate involvement of both influx and efflux transporters in vivo in gastrointestinal absorption of celiprolol in mice. Plasma concentration of celiprolol (3 mg/kg) after oral administration was mostly under the limit of quantification in wild mice, whereas that in mdr1a/b knockout (mdr1a/b(-/-)) mice was much more obvious, indicating P-glycoprotein-mediated efflux. Then, the oral absorption of celiprolol in mdr1a/b(-/-) mice was further examined to investigate influx transport mechanism with avoiding effect of P-glycoprotein. Coadministration of bromosulfophthalein (BSP), an inhibitor of various influx transporters including organic anion transporting polypeptide (OATP) reduced plasma celiprolol concentration. Inhibition by BSP of celiprolol uptake from apical membranes was confirmed in Ussing-type chamber of small intestinal tissues. Uptake of celiprolol by human small intestinal transporter OATP-A/1A2 was also confirmed in Xenopus Laevis oocytes. Interestingly, OATP-A/1A2 accepts various beta-blockers including acebutolol, atenolol and sotalol, oral absorption of which is inhibited by coadministration of citrus juice or telithromycin in human. Taken together, these findings have suggested fundamental role of influx transport system(s) in oral absorption of celiprolol.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D017272:Celiprolol / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013448:Sulfobromophthalein / Q000494:pharmacology; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D027361:Organic Anion Transporters; D013448:Sulfobromophthalein; D017272:Celiprolol