Search

We previously encountered a patient with epilepsy who exhibited rapid elimination of sustained-release valproic acid (VPA) administered at the dose of 2.8 g/d as a sodium salt. The purpose of this study was to clarify the relationship between the VPA elimination rate and the proportion of the dose excreted in urine as its glucuronide conjugate (VPA-G) in epileptic patients. Twenty-four-hour urine was collected from four epileptic patients who had taken VPA orally (age: 16-39 y, weight: 50-63 kg, dose: 1.0-2.8 g/d). VPA and its metabolites were detected by gas chromatography-mass spectrometry. The amounts of VPA, VPA-G, 3-keto VPA, and 3-OH VPA excreted in the 24-h urine were 1.8-13.2, 178-2158, 125-320, and 8.6-18.7 mg (converted into VPA), respectively, and 0.2-0.5, 20.5-88.7, 5.8-18.7, and 0.6-1.0% of the dose administered, respectively. The dose of VPA correlated well with the proportion of the dose excreted in urine as VPA-G in each patient, and the patients administered a high dose excreted a large amount of VPA-G in the urine. Thus, differences in the VPA-G production rate may be one of the major variable factors affecting the elimination of administered VPA. We also present a dynamic model of VPA in the kidney which may explain the VPA elimination phenomena in humans on the basis of the data obtained here regarding the concentrations of VPA and its metabolites in plasma and their urinary excretion levels.

The urinary excretion of valproic acid (VPA) and its metabolites (3-keto VPA, 3-OH VPA, and VPA-glucuronide) in 6 epileptic patients was studied using gas chromatography-mass spectrometry. The amount of VPA and 3-OH VPA excreted in the urine was low (0.1-0.5% of the dose of VPA and 0.6-1.5% of the dose of 3-OH administered). The amount of 3-keto VPA and glucuronide (VPA-Glu) excreted was marked (5.8-26.2% and 13.1-88.7% of the dose of VPA administered, respectively). The urinary excretion of VPA and its metabolites by patients who have taken a normal amount of a VPA preparation was almost the same as that of healthy volunteers. Two epileptic patients who took a large amount of the VPA preparation showed a high excretion of VPA-Glu without an increase in their plasma VPA-Glu.