PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF (E)-2-ENE VALPROYL DERIVATIVES OF GLYCINE AND VALPROYL DERIVATIVES OF NIPECOTIC ACID

GABA is a major inhibitory neurotransmitter in mammals, whose uptake i n glial cells is inhibited by nipecotic acid. In addition to GABA, gly cine is an important inhibitory neurotransmitter. Valproic acid (VPA) is one of the four established antiepileptics and (E)-2-ene valproic a cid ((E)-2-ene VPA) is its major active metabolite. The described stru cture-pharmacokinetic-pharmacodynamic relationship (SPPR) study explor ed the possiblity of utilizing valproyl derivatives of glycine and nip ecotic acid as new antiepileptics. The pharmacokinetics and pharmacody namics (anticonvulsant activity and neurotoxicity) of the following co njugation products were investigated: (E)-2-ene valproyl glycinamide ( between (E)-2-ene VPA and glycinamide) and valproyl nipecotic acid and valproyl nipecotamide (between VPA and nipecotic acid). Out of the in vestigated compounds only (E)-2-ene valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharma cokinetic and pharmacodynamic profile. (E)-2-ene valproyl glycinamide was more potent than VPA and showed an activity and a safety margin si milar to those of its analogous compound valproyl glycinamide. The inv estigated valproyl derivatives did not operate as chemical drug delive ry systems (CDDSs) of glycine or nipecotic acid, but, rather, acted as drugs on their own. (E)-2-ene valproyl glycinamide was partially excr eted unchanged in the urine (f(e) = 7.4%), while its urinary metabolit e was (E)-2-ene valproyl glycine. Unlike the new antiepileptic tiagabi ne, in which nipecotic acid is attached to 4,4-di-(3-methylthien-2-yl) -3-butenyl and yields an active compound, the conjugation between nipe cotic acid or its amide and VPA yielded inactive entities. In contrast to nipecotic acid, the conjugation between VPA or (E)-2-ene VPA and g lycinamide gave two active compounds with similar pharmacokinetic and pharmacodynamic profiles.