Anderson G D, Acheampong A A, Wilensky A J, Levy R H
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Epilepsia. 1992 Jul-Aug;33(4):736-42. doi: 10.1111/j.1528-1157.1992.tb02355.x.
Valproate (VPA) therapy has been associated with a rare but fatal hepatotoxicity. 4-ene-VPA and 2(E),4-diene-VPA, unsaturated metabolites of VPA, are hepatotoxins several times more potent than VPA. In a previous study, a dose-dependent excretion of hepatotoxic metabolites was noted in patients receiving VPA. Our study was designed to evaluate the effect of dose on VPA metabolism under controlled conditions. Nineteen healthy volunteers sequentially received three different daily doses of VPA (250, 500, and 1,000 mg). Each dose was given twice daily for 4 days. Urine was collected for one dosage interval (12 h) at steady state for each dose and assayed for 15 VPA metabolites by gas chromatography/mass spectrometry (GCMS). Blood samples were also obtained from eight of the subjects, and VPA was assayed by GCMS. No effect of dose was noted on total plasma clearance. There was a significant dose-dependent decrease in intrinsic hepatic clearance. The intrinsic formation clearance (Clf) of the 4-ene-VPA pathway showed a statistically significant dose-dependent increase (0.22, 0.33, 0.40 ml/h/kg). The corresponding percentage of dose recovered as 4-ene-VPA and its sequential metabolites showed significant dose-dependent increases (0.15, 0.27, 0.62%). The role of VPA dose in the pathogenesis of hepatotoxicity may be more important than was previously believed.
丙戊酸盐（VPA）治疗与一种罕见但致命的肝毒性有关。VPA的不饱和代谢产物4-烯-VPA和2（E），4-二烯-VPA是比VPA毒性强几倍的肝毒素。在先前的一项研究中，接受VPA治疗的患者出现了肝毒性代谢产物的剂量依赖性排泄。我们的研究旨在评估在受控条件下剂量对VPA代谢的影响。19名健康志愿者依次接受三种不同的每日VPA剂量（250、500和1000毫克）。每种剂量每天给药两次，共4天。在每种剂量的稳态下收集一个给药间隔（12小时）的尿液，并通过气相色谱/质谱法（GCMS）分析15种VPA代谢产物。还从8名受试者中采集了血样，并通过GCMS分析VPA。未发现剂量对总血浆清除率有影响。肝内在清除率有显著的剂量依赖性降低。4-烯-VPA途径的内在生成清除率（Clf）显示出统计学上显著的剂量依赖性增加（0.22、0.33、0.40毫升/小时/千克）。作为4-烯-VPA及其后续代谢产物回收的相应剂量百分比显示出显著的剂量依赖性增加（0.15、0.27、0.62%）。VPA剂量在肝毒性发病机制中的作用可能比以前认为的更为重要。
