Hadad S, Bialer M
Department of Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Pharm Res. 1995 Jun;12(6):905-10. doi: 10.1023/a:1016277507865.
To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach.
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.
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.
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.
通过结构-药代动力学-药效学关系（SPPR）方法，探索将γ-氨基丁酸（GABA）和甘氨酸的丙戊酰衍生物用作新型抗癫痫药物的可能性。
研究了丙戊酸（VPA）、甘氨酸和GABA的以下四种共轭产物的药代动力学和药效学（抗惊厥活性和神经毒性）：丙戊酰甘氨酸、丙戊酰甘氨酰胺、丙戊酰GABA和丙戊酰加巴酰胺。
由于其较好的药代动力学特征，仅丙戊酰甘氨酰胺在小鼠和大鼠中均显示出良好的抗惊厥谱。丙戊酰甘氨酰胺比主要抗癫痫药物之一——VPA更有效，并且在活性和神经毒性之间表现出更好的差异。丙戊酰甘氨酸和丙戊酰GABA部分以原形经尿液排泄（fe分别为50%和34%），而酰胺衍生物的尿液代谢产物为丙戊酰甘氨酸和丙戊酰GABA。
所研究的四种丙戊酰衍生物并非作为甘氨酸或GABA的化学药物递送系统（CDDS）发挥作用，而是自身作为药物起作用。当前研究证明了SPPR方法在完整动物中开发和选择强效抗癫痫化合物方面的益处，这不仅基于其内在的药效学活性，还基于其更好的药代动力学特征。
