Kinetics of quinolone antibiotics in rats: efflux from cerebrospinal fluid to the circulation.
OBJECTIVE
An active transport system, which pumps quinolone antimicrobial agents (quinolones) from cerebrospinal fluid (CSF) to systemic blood, exists at the choroid plexus, an epithelial tissue that forms the blood-CSF barrier (BCSFB). The present study was carried out to clarify the contribution of this transport system to the disposition of quinolones in the central nervous system.


METHODS
Six quinolones were administered intracerebroventricularly to rats and their elimination from the CSF was examined. The inhibitory effect of probenecid and quinolones on the efflux of fleroxacin from the CSF was also examined. Probenecid or two types of quinolone (AM-1155, pefloxacin) were co-administered intracerebroventricularly with fleroxacin.


RESULTS
The elimination clearance from the CSF for norfloxacin, AM-1155, fleroxacin, ofloxacin, sparfloxacin and pefloxacin was 14, 22, 21, 20, 47 and 35 microliters/min/rat, respectively. An approximately 3.5-fold difference was thus observed between norfloxacin and sparfloxacin. These values were 4- to 14-fold larger than the [14C]mannitol clearance. Furthermore, the elimination clearance of quinolones from the CSF was 7- to 60-fold larger than the active efflux clearance at the BCSFB estimated from our previous in vitro data. Co-administration of AM-1155, pefloxacin and probenecid did not inhibit the elimination of fleroxacin from the CSF.


CONCLUSIONS
The active transport system at the BCSFB plays only a small part in the elimination of quinolones from the CSF. Passive diffusion via the BCSFB and diffusion across the ependymal surface into brain extracellular fluid, followed by efflux across the blood-brain barrier, may be the predominant pathway for quinolone elimination from the CSF.
Ooie
T
T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Suzuki
H
H
Terasaki
T
T
Sugiyama
Y
Y
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics*; D001692:Biological Transport; D002831:Choroid Plexus / Q000378:metabolism; D016576:Fleroxacin / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D024841:Fluoroquinolones; D007276:Injections, Intraventricular; D008297:Male; D011339:Probenecid / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D015363:Quinolones / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D015366:Pefloxacin
D042462:4-Quinolones; D000890:Anti-Infective Agents; D016576:Fleroxacin; D024841:Fluoroquinolones; D011339:Probenecid; D015363:Quinolones; D015366:Pefloxacin