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 pharmacokinetic-pharmacodynamic relationship (SPPR) approach.
METHODS: The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four conjugation products of valproic acid (VPA), glycine and GABA were investigated: valproyl glycine, valproyl glycinamide, valproyl GABA and valproyl gabamide.
RESULTS: Only valproyl 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 showed a better margin between activity and neurotoxicity. Valproyl glycine and valproyl GABA were partially excreted unchanged in the urine (fe = 50% and 34%, respectively), while the urinary metabolites of the amide derivatives were valproyl glycine and valproyl GABA.
CONCLUSIONS: The four investigated valproyl derivatives did not operate as chemical 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 compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.