Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation
Ogawa, M.; Suzuki, H.; Sawada, Y.; Hanano, M.; Sugiyama, Y.
American Journal of Physiology 266(2 Pt 2): R392-R399
1994
ISSN/ISBN: 0002-9513 PMID: 8141395 Document Number: 433666
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 (K-m) = 43.0 +- 17.8 mu-M, maximum velocity (V-max) = 619 +- 286 pmol cntdot min-1 cntdot 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 (K-m = 58 mu-M, V-max = 504 pmol cntdot min-1 cntdot 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 (K-i) values obtained for these ligands in vivo and in vitro (r = 0.94, P lt 0.01). These results indicate 1) that the choroid plexus is the predominant site for the elimination of organic anions from the CSF and 2) that the isolated choroid plexus can be a useful tool to predict the in vivo elimination clearance for organic anions from the CSF.