title: Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier.
abstract: The distribution of HSR-903, a new quinolone antibacterial agent, to the brain after i.v. administration to rats was low compared with that to other tissues. The blood-brain barrier permeability to HSR-903 determined by the brain perfusion method was low, and increased nonlinearly with increasing concentration of HSR-903 in the perfusate. When the brain-to-plasma concentration ratio (Kp, brain) was measured in mdr1a gene-knockout mice, the value was 8 times higher than that in normal mice. The uptake of [14C]HSR-903 by multidrug-resistant K562/ADM cells, which express P-glycoprotein (P-gp), was significantly lower than that by the drug-sensitive parent K562 cells. In addition, the uptake of [14C]HSR-903 by K562/ADM cells was significantly increased in the presence of cyclosporin A and ATP-depleting agents. These observations support the idea that P-gp participates in HSR-903 efflux from the brain. The steady-state uptake of HSR-903 by a monolayer of primary cultured bovine brain capillary endothelial cells was increased in the presence of several quinolone antibacterial agents or anionic compounds, such as 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, and in bicarbonate ion-free medium, as well as by P-gp inhibitors (cyclosporin A and quinidine). These results suggested that the efflux of HSR-903 proceeds at least partly via an anion-sensitive efflux transport mechanism as well as via P-gp. In conclusion, the low brain distribution of the new quinolone antibacterial agent HSR-903 can be ascribed to multiple efflux mechanisms including P-gp and an unidentified anion-sensitive transporter operating in the brain capillary endothelial cells that constitute the blood-brain barrier.
authors.affiliation: Department of Pharmacobio-dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: I
authors.initials: I
authors.lastname: Tamai
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: O
authors.initials: O
authors.lastname: Nagata
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001639:Bicarbonates / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002196:Capillaries; D002417:Cattle; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D024841:Fluoroquinolones; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D015363:Quinolones / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D001639:Bicarbonates; D024841:Fluoroquinolones; D015363:Quinolones; C106426:olamufloxacin; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid