Characterization of the transport properties of a quinolone antibiotic, fleroxacin, in rat choroid plexus.
OBJECTIVE
It is reported that the cerebrospinal fluid (CSF) to plasma unbound concentration ratio of fleroxacin at steady-state is approximately 0.5 in experimental animals. These results can be accounted for by assuming the presence of an active transport system for the efflux of this compound across the choroid plexus. In the present study, the transport system for fleroxacin was characterized in isolated rat choroid plexus.


METHODS
Choroid plexus was isolated from the lateral ventricles of rats. The accumulation of [14C] fleroxacin or [3H] benzylpenicillin by the choroid plexus was examined by the centrifugal filtration method.


RESULTS
The accumulation of [14C] fleroxacin by the rat isolated choroid plexus was significantly inhibited by metabolic inhibitors (rotenone, 30 microM and carbonyl cyanide rho-trifluorometh oxyphenylhydrazone (FCCP), 100 microM) and sulfhydryl reagent (p-chloromercuribenzenesulfonic acid (PCMBS), 100 microM). This accumulation was composed of a saturable component (Vmax = 240 pmol.min-1.microliter tissue-1, Km = 664 microM) and non-saturable one (P = 0.424 min-1.microliter tissue-1). Accumulation of fleroxacin was competitively inhibited by benzylpenicillin and probenecid with Ki values of 29 microM and 51 microM, respectively. These values are comparable with the Km of benzylpenicillin transport and the Ki of probenecid for the benzylpenicillin transport at the choroid plexus, respectively. Furthermore, fleroxacin inhibited competitively the accumulation of [3H] benzylpenicillin with a Ki of 384 microM, a value comparable with the Km of [14C] fleroxacin transport.


CONCLUSIONS
Fleroxacin and benzylpenicillin showed mutual competitive inhibition, suggesting that both are transported via a common transport system in the choroid plexus and are pumped out from CSF into the circulation.
Ooie
T
T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Suzuki
H
H
Terasaki
T
T
Sugiyama
Y
Y
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology; D002731:4-Chloromercuribenzenesulfonate / Q000494:pharmacology; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D001693:Biological Transport, Active; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016576:Fleroxacin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D017136:Ion Transport; D007553:Isotope Labeling; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D010400:Penicillin G / Q000493:pharmacokinetics / Q000494:pharmacology; D010406:Penicillins / Q000493:pharmacokinetics / Q000494:pharmacology; D011339:Probenecid / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012076:Renal Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D010406:Penicillins; D012076:Renal Agents; D013439:Sulfhydryl Reagents; D014475:Uncoupling Agents; D012402:Rotenone; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D010042:Ouabain; D002731:4-Chloromercuribenzenesulfonate; D016576:Fleroxacin; D011339:Probenecid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D010400:Penicillin G