Cefoselis is a widely used
beta-lactam antibiotic, but occasionally induces
seizures and convulsion in elder and
renal failure patients. However,
beta-lactams are known not to pass through the blood-brain barrier (BBB). In this study, we examined the BBB penetration of
cefoselis in normal and
renal failure rats by means of brain microdialysis.
Cefoselis was dose-dependently appeared in brain extracellular fluid in proportion to its blood level. The elimination constant from brain extracellular fluid (apparent) was slightly lower than that from blood. These results indicated that
cefoselis might penetrate the BBB or be discharged by a certain transport system. In contrast to the result of
cefoselis,
cefazolin, a leading
drug of
cephalosporins, could not be detected in the brain extracellular fluid after an
intravenous injection. In renal dysfunction rats, the elimination half-lives of
cefoselis from both blood and brain were extensively prolonged. This would be one of responsible factors inducing
seizures seen in patients. However, the additional factor, such as decrease in brain function related to aging, would be involved in
seizures in patient received
cefoselis, because an extremely high dose was required to induce
seizures even in
renal failure rats. A local administration of
cefoselis into the hippocampus through the microdialysis probe caused a striking elevation of extracellular
glutamate, with a minimum increase in
gamma-aminobutyric acid (
GABA). However, a systematic
cefoselis administration via the tail vein did not elevate extracellular
glutamate and
GABA concentrations in the hippocampus of
renal failure rats that exhibited marked
seizures. These results suggested that not the stimulation of
glutamate release, but the blockade of
GABA receptors might be responsible for the seizure induced by
cefoselis.