PHARMACOKINETIC ANALYSIS AND ANTIEPILEPTIC ACTIVITY OF N-VALPROYL DERIVATIVES OF GABA AND GLYCINE

Purpose. To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharm acokinetic-pharmacodynamic relationship (SPPR) approach. Methods. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neu rotoxicity) of the following four conjugation products of valproic aci d (VPA), glycine and GABA were investigated: valproyl glycine, valproy l glycinamide, valproyl GABA and valproyl gabamide. Results. Only valp royl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic profile. Valproyl glycinamide was more potent than one of the major antiepileptic agents - VPA and s howed a better margin between activity and neurotoxicity. Valproyl gly cine and valproyl GABA were partially excreted unchanged in the urine (fe=50% and 34%, respectively), while the urinary metabolites of the a mide derivatives were valproyl glycine and valproyl GABA. Conclusions. The four investigated valproyl derivatives did not operate as chemica l drug delivery systems (CDDS) of glycine or GABA, but acted rather as drugs on their own. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic comp ound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.