abu Salach O, Hadad S, Haj-Yehia A, Sussan S, Bialer M
Department of Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Pharm Res. 1994 Oct;11(10):1429-34. doi: 10.1023/a:1018943906510.
Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents--valproic acid and showed a better margin between activity and neurotoxicity. 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 unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
除γ-氨基丁酸外，甘氨酸是最重要的神经递质氨基酸之一。所描述的结构-药代动力学-药效学关系（SPPR）研究探索了利用甘氨酸的邻苯二甲酰衍生物作为新型抗癫痫药物的可能性。这是通过研究以下四种邻苯二甲酰亚胺衍生物的药代动力学和药效学（抗惊厥活性和神经毒性）来进行的：邻苯二甲酰甘氨酸、邻苯二甲酰甘氨酰胺、N,N-二乙基邻苯二甲酰甘氨酰胺和N,N-二异丙基邻苯二甲酰甘氨酰胺。邻苯二甲酰甘氨酸未表现出抗惊厥活性，可能是由于其药代动力学较差、清除率高、分布容积低和半衰期短。三种甘氨酰胺衍生物表现出抗惊厥活性，并且与邻苯二甲酰甘氨酸相比，具有更好的药代动力学特征、更长的半衰期和平均驻留时间。邻苯二甲酰甘氨酰胺比主要抗癫痫药物之一丙戊酸更有效，并且在活性和神经毒性之间表现出更好的差异。所研究的四种邻苯二甲酰甘氨酸衍生物并非作为甘氨酸的化学药物递送系统（CDDS）发挥作用，而是本身作为药物起作用。邻苯二甲酰甘氨酸以原形经尿液排泄，而甘氨酰胺衍生物的尿液代谢产物为邻苯二甲酰甘氨酸和邻苯二甲酰甘氨酰胺。在这一系列类似的邻苯二甲酰亚胺衍生物中，微小的化学变化极大地影响了化合物的药代动力学。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。（摘要截断于250字）
