Katayama Hirokazu, Mizukami Kohki, Yasuda Manami, Hatae Tomomi
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, Japan.
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, Japan.
J Pharm Sci. 2016 Oct;105(10):3199-3204. doi: 10.1016/j.xphs.2016.06.024. Epub 2016 Aug 4.
The long-term administration of valproic acid (VPA) may decrease the plasma concentrations of l-carnitine in epileptic patients. l-Carnitine is essential for the β-oxidation of fatty acids. The aim of this study is to determine whether endogenous l-carnitine affects the pharmacokinetics of VPA in l-carnitine-deficient (CD) rats. An l-carnitine deficiency was induced in rats using sodium pivalate. The pharmacokinetics of VPA were examined following its intravenous or oral administration to rats. The plasma and urine concentrations of VPA and its metabolites were determined using gas chromatography-mass spectrometry methods. Plasma VPA concentrations were slightly higher in CD rats than in control rats, whereas no significant differences were observed in the area under the curve or mean residence times of VPA between the 2 groups. After i.v. administration, the slope of the elimination phase (k) was significantly higher in CD rats than in control rats (p < 0.01). Some of the β-oxidation metabolites of VPA in plasma and urine decreased, while the glucuronide metabolites of VPA in urine increased complementarily in CD rats. Based on these results, it was concluded that hypocarnitinemia could affect the pharmacokinetics of VPA.
长期服用丙戊酸（VPA）可能会降低癫痫患者血浆中左旋肉碱的浓度。左旋肉碱对脂肪酸的β氧化至关重要。本研究的目的是确定内源性左旋肉碱是否会影响左旋肉碱缺乏（CD）大鼠体内VPA的药代动力学。使用特戊酸钠诱导大鼠出现左旋肉碱缺乏。在大鼠静脉注射或口服VPA后检测其药代动力学。采用气相色谱-质谱法测定VPA及其代谢产物在血浆和尿液中的浓度。CD大鼠血浆中的VPA浓度略高于对照大鼠，而两组之间VPA的曲线下面积或平均驻留时间未观察到显著差异。静脉注射后，CD大鼠消除相斜率（k）显著高于对照大鼠（p < 0.01）。CD大鼠血浆和尿液中VPA的一些β氧化代谢产物减少，而尿液中VPA的葡萄糖醛酸代谢产物则相应增加。基于这些结果，得出结论：低肉碱血症可能会影响VPA的药代动力学。
