Diurnal variation in valproic acid clearance.

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.