Effects of Carnitine on Valproic Acid Pharmacokinetics in Rats

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.