COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF PHTHALOYLGLYCINE DERIVATIVES WITH POTENTIAL ANTIEPILEPTIC ACTIVITY

Glycine, in addition to GABA, is one of the most important neurotransm itter amino acids. The described structure pharmacokinetic pharmacodyn amic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carri ed out by investigating the pharmacokinetics and pharmacodynamics (ant iconvulsant activity and neurotoxicity) of the following four phthalim ide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phth aloyl glycine did not demonstrate anticonvulsant activity, possibly be cause of its poor pharmacokinetics, high clearance, low volume of dist ribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, long er half life and mean residence time, than phthaloyl glycine. Phthaloy l glycinamide was more potent than one of the major antiepileptic agen ts-valproic acid and showed a better margin between activity and neuro toxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchange d in the urine while the urinary metabolites of the glycinamide deriva tives were phthaloyl glycine and phthaloyl glycinamide. In this analog ous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. The current study demon strates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacoki netic profile.