Faculty of Medicine, Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Epilepsia. 2014 Dec;55(12):1944-52. doi: 10.1111/epi.12857. Epub 2014 Nov 29.
2-Ethyl-3-methylbutyl-carbamate (EMC) and 2-isopropylpentyl-carbamate (IPC) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC and IPC are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK) and pharmacodynamic (PD anticonvulsant activity) profile of EMC and IPC individual enantiomers.
The anticonvulsant activity of EMC and IPC individual enantiomers was evaluated in several anticonvulsant rodent models including maximal electroshock (MES), 6 Hz psychomotor, subcutaneous (pentylenetetrazole) (scMet), and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD relationship of EMC and IPC individual enantiomers was evaluated following intraperitoneal administration (50 mg/kg) to rats. Induction of neural tube defects (NTDs) was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs.
In mice and rats, (2S)-EMC exhibited anticonvulsant activity similar to that of racemic EMC in the MES and scMet tests, whereas in the 6 Hz test, racemic EMC was more potent than its two individual enantiomers. Racemic EMC exhibited a potent activity in the soman-induced SE model when administered 5 and 20 min after seizure onset with median effective dose (ED50 ) values of 33 and 48 mg/kg, respectively. (2R)-IPC and (2S)-IPC exhibited ED50 values similar to those of racemic IPC in the mouse and rat MES and scMet models. (2R)-IPC had similar ED50 values on the 6 Hz tests. Racemic IPC had an ED50 value of 107 mg/kg in the pilocarpine-induced SE model when given 30 min after seizure onset. Racemic EMC and IPC and their enantiomers had similar clearance (3.8-5.5 L/h/kg) and short half-life (<1 h). EMC and its enantiomers did not cause NTDs at doses 3-10 times higher than their anticonvulsant ED50 values.
EMC and IPC did not exhibit enantioselective PK, a fact that may contribute to their nonenantioselective activity in any of the anticonvulsant models. The nonsignificant difference between racemic EMC and racemic IPC and their enantiomers, suggests that their wide spectrum of anticonvulsant activity is likely to be caused by multiple mechanisms of action.
2-乙基-3-甲基丁基氨基甲酸酯（EMC）和 2-异丙基戊基氨基甲酸酯（IPC）是丙戊酸最有效的抗惊厥氨基甲酸酯衍生物之一。EMC 和 IPC 是手性化合物。因此，本研究的目的是比较评估 EMC 和 IPC 单个对映异构体的药代动力学（PK）和药效学（PD 抗惊厥活性）特征。
在几种抗惊厥啮齿动物模型中评估了 EMC 和 IPC 单个对映异构体的抗惊厥活性，包括最大电休克（MES）、6 Hz 运动、皮下（戊四氮）（scMet）和毛果芸香碱诱导和梭曼诱导的癫痫持续状态（SE）。在大鼠中腹腔给予（50 mg/kg）后，评估了 EMC 和 IPC 单个对映异构体的 PK-PD 关系。在对致畸形物诱导的神经管缺陷（NTDs）高度敏感的小鼠品系中评估了 NTDs 的诱导。
在小鼠和大鼠中，（2S）-EMC 在 MES 和 scMet 试验中表现出与外消旋 EMC 相似的抗惊厥活性，而在 6 Hz 试验中，外消旋 EMC 比其两个单独的对映异构体更有效。在梭曼诱导的 SE 模型中，当在发作后 5 和 20 分钟给予外消旋 EMC 时，其具有很强的活性，中位数有效剂量（ED50）值分别为 33 和 48 mg/kg。（2R）-IPC 和（2S）-IPC 在小鼠和大鼠的 MES 和 scMet 模型中表现出与外消旋 IPC 相似的 ED50 值。（2R）-IPC 在 6 Hz 试验中具有相似的 ED50 值。当在发作后 30 分钟给予时，外消旋 IPC 在毛果芸香碱诱导的 SE 模型中具有 107 mg/kg 的 ED50 值。外消旋 EMC 和 IPC 及其对映异构体的清除率（3.8-5.5 L/h/kg）和半衰期（<1 h）相似。EMC 和其对映异构体在高于其抗惊厥 ED50 值 3-10 倍的剂量下不会引起 NTDs。
EMC 和 IPC 没有表现出对映体选择性 PK，这一事实可能有助于它们在任何抗惊厥模型中表现出非对映体活性。外消旋 EMC 与外消旋 IPC 及其对映异构体之间无显着差异表明，它们广泛的抗惊厥活性可能是由多种作用机制引起的。
