title: Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein.
abstract: Transport of quinolone antimicrobials and the contribution of the secretory transporter P-glycoprotein were studied in-vivo and in-vitro. In rat intestinal tissue (Ussing chambers method) and human Caco-2 cells (Transwell method), grepafloxacin showed secretory-directed transport. In both experimental systems, the secretory-directed transport was decreased by ciclosporin A, an inhibitor of P-glycoprotein, and probenecid, an inhibitor of anion transport systems. This suggested the contribution of P-glycoprotein and anion-sensitive transporter(s). The involvement of P-glycoprotein was investigated by using a P-glycoprotein over-expressing cell line, LLC-GA5-COL150, and P-glycoprotein-gene-deficient mice (mdr1a(-/-)/1b(-/-) mice). LLC-GA5-COL150 cells showed secretory-directed transport of grepafloxacin, while the parent cell line, LLC-PK1, did not. The secretory-directed transport of sparfloxacin and levofloxacin was also detected in LLC-GA5-COL150 cells. In the mdr1a(-/-)/1b(-/-) mice, the intestinal secretory clearance was smaller than that in wild-type mice after intravenous administration of grepafloxacin. Moreover, the absorption from an intestinal loop in mdr1a(-/-)/1b(-/-) mice was larger than that in wild-type mice. Accordingly, it appears that some quinolones are transported by secretory transporters, including P-glycoprotein. The involved transporters function in-vivo not only to transport grepafloxacin from blood to intestine but also to limit its intestinal absorption.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Naruhashi
authors.forename: I
authors.initials: I
authors.lastname: Tamai
authors.forename: N
authors.initials: N
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Muraoka
authors.forename: Y
authors.initials: Y
authors.lastname: Sai
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000494:pharmacology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002460:Cell Line; D024841:Fluoroquinolones; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C095122:multidrug resistance protein 3