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 r emacemide and its pharmacologically active metabolite FPL12495 [(+/-)- 1-methyl-1,2-diphenylethylamine monohydrochloride] were 51 and 130%, r espectively. The BUI of [C-14] remacemide and [C-14]FPL12495 were not affected by increasing amounts of unlabeled remacemide or FPL12495, re spectively. Like wise, the BUI of remacemide was not affected by dl-am phetamine or beta-phenethylamine. A mixture of [H-3]remacemide hydroch loride (H-3 label in the glycine moiety) and [C-14]remacemide hydrochl oride (C-14 label in 1,2-diphenyl-2-aminopropane moiety) was administe red by intracarotid injection. The ratio of C-14/H-3 in the brain was equal to that in the injection mixture, indicating that remacemide ent ers the brain intact. HPLC analysis of brain extracts of rats given [C -14] remacemide hydrochloride by intracarotid injection revealed that 97.8 +/- 0.2% (mean +/- SD) of the radioactivity was present as remace mide, whereas 1.9 +/- 0.2% of the radioactivity was present as FPL1249 5. Finally, in vitro studies revealed that remacemide is hydrolyzed by whole-brain homogenates to the pharmacologically active metabolite FP L12495. Data indicate that remacemide enters the brain by passive diff usion and undergoes deglycination at the blood-brain barrier or within the brain to give FPL12495.