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.

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…Griffiths et al 88 Similar studies by Naruhashi et al 89 demonstrated that grepafloxacin showed secretory-directed transport which was decreased by cyclosporin A, an inhibitor of P-glycoprotein, and probenecid, an inhibitor of anion transport systems. This suggested contributions of P-glycoprotein and anion-sensitive transporter(s).…”

“…Moreover, the absorption from an intestinal loop in mdr1a(-/-)/1b(-/-) mice was larger than that in wild-type mice. 89 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.…”

Pharmacokinetic Analysis of Transcellular Transport of Levofloxacin across LLC-PK1 and Caco-2 Cell Monolayers

“…Plausible candidates for efflux transporters of levofloxacin were P-gp, MRP, and BCRP. [17][18][19] Naruhashi et al reported that the secretory transport of levofloxacin in Caco-2 cells was diminished by a P-gp inhibitor cyclosporin A, a MRP modulator probenecid, and the combination of the two compounds. 17) Yamaguchi et al, however, reported that cyclosporin A and probenecid did not affect the basolateral-to-apical transport of levofloxacin in Caco-2 cells.…”

“…[17][18][19] Naruhashi et al reported that the secretory transport of levofloxacin in Caco-2 cells was diminished by a P-gp inhibitor cyclosporin A, a MRP modulator probenecid, and the combination of the two compounds. 17) Yamaguchi et al, however, reported that cyclosporin A and probenecid did not affect the basolateral-to-apical transport of levofloxacin in Caco-2 cells. 18) On the other hand, Xia et al reported that BCRP was expressed at the apical membrane in Caco-2 cells, and transported its substrate, such as estrone-3-sulfate and methotrexate.…”

Screening of Antibiotics That Interact with Organic Anion-Transporting Polypeptides 1B1 and 1B3 Using Fluorescent Probes

“…P-glycoprotein (ATP-binding cassette B1 (ABCB1)) is known to limit the oral bioavailability of grepafloxacin and salinomycin. [1][2][3] Breast cancer resistance protein (BCRP/ABCG2) affects the oral bioavailability of quinolone antibacterial drugs. 4) P-glycoprotein and BCRP expressed at the brush-border membrane in the intestine work as an absorption barrier of these drugs.…”