Brain uptake and biotransformation of remacemide hydrochloride, a novel anticonvulsant.
The brain uptake and biotransformation of remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide monohydrochloride; FPL 12924AA] were studied in the rat. The brain uptake indices (BUI) for remacemide and its pharmacologically active metabolite FPL12495 [(+/-)-1-methyl-1,2-diphenylethylamine monohydrochloride] were 51 and 130%, respectively. The BUI of [14C] remacemide and [14C]FPL12495 were not affected by increasing amounts of unlabeled remacemide or FPL12495, respectively. Likewise, the BUI of remacemide was not affected by dl-amphetamine or beta-phenethylamine. A mixture of [3H]remacemide hydrochloride (3H label in the glycine moiety) and [14C]remacemide hydrochloride (14C label in 1,2-diphenyl-2-aminopropane moiety) was administered by intracarotid injection. The ratio of 14C/3H in the brain was equal to that in the injection mixture, indicating that remacemide enters the brain intact. HPLC analysis of brain extracts of rats given [14C] remacemide hydrochloride by intracarotid injection revealed that 97.8 +/- 0.2% (mean +/- SD) of the radioactivity was present as remacemide, whereas 1.9 +/- 0.2% of the radioactivity was present as FPL12495. Finally, in vitro studies revealed that remacemide is hydrolyzed by whole-brain homogenates to the pharmacologically active metabolite FPL12495. Data indicate that remacemide enters the brain by passive diffusion and undergoes deglycination at the blood-brain barrier or within the brain to give FPL12495.
Heyn
H
H
Department of Pharmacology, University of Rochester, NY 14642.
McCarthy
D J
DJ
Curry
S H
SH
Eisman
M S
MS
Anders
M W
MW
D000081:Acetamides / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D008297:Male; D010627:Phenethylamines / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013462:Sulfur Radioisotopes
D000081:Acetamides; D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D010627:Phenethylamines; D013462:Sulfur Radioisotopes; C089135:FPL 12495; C067553:remacemide