Pharmacokinetics and metabolism of 14C-levetiracetam, a new antlepileptic agent, in healthy volunteers
Pharmacokinetics and metabolism of 14C-levetiracetam, a new antlepileptic agent, in healthy volunteers
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DOI：
10.1007/s00228-003-0655-6
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发表时间：
2003-11-01
影响因子：
2.9
通讯作者：
Baltes, E
中科院分区：
文献类型：
--
作者：
Benedetti, MS;Whomsley, R;Baltes, E
左乙拉西坦的吸收、处置和代谢。一种新的抗癫痫药物，已经在男性健康志愿者口服单剂量的C-14标记分子后进行了研究。由于药物代谢过程中可能发生手性转化，因此还研究了左乙拉西坦和/或其水解产生的主要代谢产物（相应的酸）的手性转化。最后，在体外左乙拉西坦水解其主要代谢产物和抑制这一反应在人体血液中进行了研究。左乙拉西坦在人体内吸收非常迅速，原型药物的血浆峰浓度出现在0.25-0.50 h。在所有测定时间点（即直至给药后48 h），原型药物占血浆放射性的百分比非常高（97-82%）。该化合物的表观分布容积接近（0.55-0.62 l/kg）全身水的体积。总体清除率（0.80-0.97 ml/min/kg）远低于标称肝血流量。原型药物的血浆消除半衰期在7.4 h至7.9 h之间变化。总放射性浓度的血浆/血液比值为1.1-1.3，表明血细胞和血浆中的放射性浓度相似。所有四名志愿者的排泄平衡都非常高。主要排泄途径为尿液，4天后平均占给药剂量的95%。尿液中存在两种主要放射性成分，原型药物和水解获得的酸，48 h后分别占剂量的66%和24%。左乙拉西坦在人血液中的水解遵循Michaelis-Menten动力学，Km和V-max值分别为435 μ M和129 pmol/min/ml血液。在本研究中研究的抑制剂中，只有对氧磷抑制左乙拉西坦水解（在100 μ M时抑制率为92%）。氧化代谢发生在人体中，尽管其占剂量的比例不超过2.5%。没有手性反转的证据。
The absorption, disposition and metabolism of levetiracetam. a new antiepileptic drug, have been investigated after a single oral dose of the C-14-labelled molecule administered to male healthy volunteers. As chiral inversion can occur during drug metabolism, the chiral inversion of levetiracetam and/or of its major metabolite produced by hydrolysis (the corresponding acid) was also investigated. Finally, the in vitro hydrolysis of levetiracetam to its major metabolite and the inhibition of this reaction in human blood have been studied. Levetiracetam was very rapidly absorbed in man, with the peak plasma concentration of the unchanged drug occurring at 0.25-0.50 h. The unchanged drug accounted for a very high percentage of plasma radioactivity (97-82%) at all the times measured, i.e. until 48 h after administration. The apparent volume of distribution of the compound was close (0.55-0.62 1/kg) to the volume of total body water. Total body clearance (0.80-0.97 ml/min/kg) was much lower than the nominal hepatic blood flow. The plasma elimination half-life of the unchanged drug varied between 7.4 h and 7.9 h. Plasma to blood ratio of total radioactivity concentrations was 1.1-1.3, showing that radioactivity concentrations were similar in blood cells and plasma. The balance of excretion was very high in all four volunteers. The predominant route of excretion was via urine, accounting for a mean of 95% of the administered dose after 4 days. Two major radioactive components were present in urine, the unchanged drug and the acid obtained by hydrolysis, accounting for 66% and 24% of the dose after 48 h, respectively. Hydrolysis of levetiracetam in human blood followed Michaelis-Menten kinetics with Km and V-max values of 435 muM and 129 pmol/min/ml blood, respectively. Among the inhibitory agents investigated in this study, only paraoxon inhibited levetiracetam hydrolysis (92% inhibition at 100 muM). Oxidative metabolism occurred in man, although it accounted for no more than 2.5% of the dose. There was no evidence of chiral inversion.