Valproic acid has temporal variability in urinary clearance of metabolites

The reasons for the intra- and interindividual variability in the clearance of valproic acid (VPA) have not been completely characterized. The aim of this study was to examine day-night changes in the clearance of 3-oxo-valpr oate (3-oxo-VPA), 4-hydroxy-valproate (4-OH-VPA), and valproic acid glucuro nides under steady state. Six diurnally active healthy male volunteers inge sted 200 mg sodium valproate 12 hourly, at 0800 and 2000, for 28 days. On t he last study day, two sequential 12-h urine samples were collected commenc ing at 2000 the evening before. Plasma samples were obtained at the end of each collection. Following alkaline hydrolysis, urine was analyzed for conc entrations of VPA, 3-oxo-VPA, and 4-OH-VPA. A separate aliquot was assayed for creatinine (CR). The plasma concentrations of VPA, 3-oxo-VPA, 2-en-VPA, and CR were determined. The analysis of VPA and its metabolites was perfor med by CC-MS. There was an increase in plasma 3-oxo-VPA concentration at 08 00, sampling as compared to 2000 sampling (p < .05). The urinary excretion of 3-oxo-VPA and VPA glucuronides were decreased between 2000 and 0800, com pared to between 0800, and 2000, by 30% and 50% respectively (p < .05). The se results indicate a nocturnal decrease in renal clearance of 3-oxo-VPA ra ther than a decrease in the beta -oxidation of VPA at night. These differen ces were not explained by differences between the sampling periods in CR ex cretion. These results indicate the importance of collecting samples of 24- h duration when studying metabolic profiles of VPA.