Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system.
The transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system (CNS) was studied using in vivo, in situ and in vitro experimental techniques. After i.v. bolus administration, the imipenem concentration in the cerebrospinal fluid (CSF) rose to a peak within 30 min and declined with time. The CSF/serum unbound concentration ratio of imipenem was 0.22 at 2 hr after i.v. administration, substantially higher than that reported for benzylpenicillin. By using an in situ brain perfusion technique, we found that imipenem was transported through the blood-brain barrier principally via passive diffusion with a permeability-surface area product comparable to that of mannitol. In vitro, imipenem was accumulated by the isolated choroid plexus via an active organic anion transport system, although much less rapidly than benzylpenicillin. In vivo, after i.c.v. administration, imipenem was cleared from the CNS in a manner comparable to that of mannitol with only a small probenecid-sensitive process. Imipenem thus has minimal affinity for the organic anion transport system in the choroid plexus, resulting in the slow elimination of this drug from the CNS. These results suggest that the difference between imipenem and benzylpenicillin in the ratio of CSF to unbound serum drug concentration is determined principally by the efflux process in the choroid plexus rather than the influx process through the blood-brain barrier.
Suzuki
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Sawada
Y
Y
Sugiyama
Y
Y
Iga
T
T
Hanano
M
M
Spector
R
R
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000378:metabolism*; D015377:Cilastatin / Q000134:cerebrospinal fluid / Q000494:pharmacology; D015378:Imipenem / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics*; D007276:Injections, Intraventricular; D008353:Mannitol / Q000134:cerebrospinal fluid; D010400:Penicillin G / Q000134:cerebrospinal fluid; D051381:Rats
D015377:Cilastatin; D008353:Mannitol; D015378:Imipenem; D010400:Penicillin G