Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation.
To examine the role of the choroid plexus in eliminating organic anions from the cerebrospinal fluid (CSF), a kinetic study was performed both in in vivo and in vitro experiments using [3H]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [3H]PCG was eliminated from the CSF much more rapidly than [14C]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [3H]PCG can be accounted for by convective loss at a rate equivalent to CSF turnover, and by diffusional loss across the ependymal surface into the brain extracellular space, respectively. Approximately two-thirds of [3H]PCG elimination was due to a saturable process [Michaelis constant (Km) = 43.0 +/- 17.8 microM, maximum velocity (Vmax) = 619 +/- 286 pmol.min-1 x rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [3H]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (Km = 58 microM, Vmax = 504 pmol.min-1 x rat-1; H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Exp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [3H]PCG in a dose-dependent manner both in vivo and in vitro. A good correlation was observed between the log inhibition constant (Ki) values obtained for these ligands in vivo and in vitro (r = 0.94, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Ogawa
M
M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Suzuki
H
H
Sawada
Y
Y
Hanano
M
M
Sugiyama
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002831:Choroid Plexus / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008353:Mannitol / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D008433:Mathematics; D008954:Models, Biological; D010400:Penicillin G / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013997:Time Factors; D014316:Tritium
D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D014316:Tritium; D008353:Mannitol; D010400:Penicillin G