KINETICS OF ACTIVE EFFLUX VIA CHOROID-PLEXUS OF BETA-LACTAM ANTIBIOTICS FROM THE CSF INTO THE CIRCULATION

Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35: R392-R399, 1994. - 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 [H-3]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [H-3]PCG was eliminated from the CSF much more rapidly than [C-14]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [H-3]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 [H-3]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.min(-1).rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [H-3]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (K-m = 58 mu M, V-max = 504 pmol.min(-1).rat(-1); H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Erp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [H-3]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 < 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.