title: Transport of gemifloxacin, a 4th generation quinolone antibiotic, in the Caco-2 and engineered MDCKII cells, and potential involvement of efflux transporters in the intestinal absorption of the drug.
abstract: The oral (po) bioavailability of gemifloxacin mesylate in rats and its possible association with efflux transporters was investigated. The apparent permeabilities (Papp) of gemifloxacin across the Caco-2 cell monolayer were 1.20 ± 0.09 × 10(-5) cm/s for apical to basal (absorptive) transport, and 2.13 ± 0.6 × 10(-5) cm/s for basal to apical (secretory) transport for a 5-500 μM concentration range, suggesting the involvement of a carrier-mediated efflux in the secretory transport. The secretory transport in Caco-2 cells was significantly decreased by MRP2 (MK571) and BCRP (Ko143) inhibitors. The secretory transport was distinct in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells, and the affinity was highest for MRP2, followed by BCRP and P-gp. The efflux was significantly decreased by verapamil and Ko143, but not significantly by MK571. The comparative po bioavailability in rats was increased by the preadministration of Ko143 (four-fold), MK571 (two-fold) and verapamil (two-fold). Efflux transporters appeared to significantly limit the bioavailability of gemifloxacin in rats, suggesting their possible contribution to the low bioavailability of the drug in the human (70%).
authors.affiliation: National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hyo-Eon
authors.initials: HE
authors.lastname: Jin
authors.forename: Boran
authors.initials: B
authors.lastname: Song
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D004285:Dogs; D024841:Fluoroquinolones / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000077735:Gemifloxacin; D006801:Humans; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009287:Naphthyridines / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D015363:Quinolones / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D026901:Membrane Transport Proteins; D009287:Naphthyridines; D015363:Quinolones; D014700:Verapamil; D000077735:Gemifloxacin