Permeability of a neuroprotective compound NS-7 into brain: comparison between normal and middle cerebral artery-occluded rats.
The pharmacokinetics of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, in brains of normal and ischemic rats were investigated. In normal rats, the concentrations of NS-7 in the cerebral cortex and striatum were more than 10-folds higher than those in plasma during 5 min and 12 h after intravenous injection. The time course changes in plasma concentration of NS-7 were fitted to the two-compartment open model, in which elimination half-life (t(1/2)beta) was 6.0 h and distribution volume (V1) was 4.4. The estimated striatal interstitial concentration of NS-7 measured by microdialysis was unexpectedly low and almost constant after intravenous injection. Subsequently, the level of NS-7 in brain was compared between sham-operated and middle cerebral artery (MCA)-occluded rats. In MCA-occluded rats, the concentrations of NS-7 in the ischemic cerebral cortex and striatum were 64-71% of those in sham-operated group at 1 h after injection, although the initial concentrations (at 2-5 min) were much lower (about 20%) in MCA-occluded rats. The t(max) was observed at 1 h after injection, which was later than that (5 min) determined in sham-operated rats. Moreover, its elimination half-life was longer in MCA-occluded rats than in sham-operated animals. From these results it is suggested that peripherally administered NS-7 readily penetrates into brain, in which it exists for the most part in parenchymal fraction. In addition, substantial amount of NS-7 may distribute to the ischemic brain regions when it was injected after MCA occlusion.
Itoh
Y
Y
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Aoki
Y
Y
Nonaka
K
K
Ukai
Y
Y
Yoshikuni
Y
Y
Kimura
K
K
D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002536:Cerebral Arteries / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010539:Permeability; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers
C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D011743:Pyrimidines; D026941:Sodium Channel Blockers