Bialer M
Department of Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Clin Pharmacokinet. 1993 Jun;24(6):441-52. doi: 10.2165/00003088-199324060-00002.
During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.
在过去几年中，抗癫痫药物库中可用药物的数量大幅增加。事实上，3种新型抗癫痫药物，即氨己烯酸、奥卡西平和拉莫三嗪，最近在几个欧洲国家获得批准。另外两种药物，非氨酯和加巴喷丁，预计不久将在美国获得批准。本综述对以下10种新型抗癫痫药物的药代动力学进行了比较评估：非氨酯、氟桂利嗪、加巴喷丁、拉莫三嗪、奥卡西平、瑞玛西胺、司替戊醇、噻加宾、托吡酯和氨己烯酸。基于其药代动力学特征，其中3种新药，即加巴喷丁、托吡酯和氨己烯酸，更具前景。它们吸收良好，主要以原形经尿液排泄，不易被酶诱导或抑制。它们的药物相互作用潜力似乎最小。约50%的非氨酯以原形排泄，其余通过代谢消除。其余药物通过葡萄糖醛酸化（拉莫三嗪）、去甘氨酸形成（瑞玛西胺）或氧化代谢（氟桂利嗪和司替戊醇）等代谢过程消除。奥卡西平和瑞玛西胺具有较高的肝脏清除率，分别生物转化为羟基和去甘氨酸代谢物，尽管存在较高的首过效应代谢，但口服给药后其代谢物的活性有助于母体药物的抗癫痫活性。加巴喷丁和奥卡西平的药代动力学表现与其最初设计意图不符。加巴喷丁作为γ-氨基丁酸（GABA）的化学药物递送系统无效，奥卡西平是其羟基代谢物的前体药物，但自身并无药理活性。然而，这两种药物在广泛的临床前和临床试验中均显示出疗效。尽管这些药物的药代动力学特征很重要，但这些特征相对于其药效学特性而言是次要的——也就是说，新型抗癫痫药物必须在癫痫患者中具有已证实的临床疗效和安全性。
