Diurnal Variation of Valproic Acid Plasma Levels and Day‐Night Reversal in Monkey

Abstract

Normal monkeys (4) equipped with an EEG plug and 2 indwelling catheters for drug infusion and sampling, respectively, were administered valproic acid (VPA) before and after a 12-h light, 12-h dark phase shift. Before day-night reversal, diurnal oscillations of VPA plasma levels under steady-state i.v. constant-rate infusions were 30-50%, with maximum concentrations during the dark phase of the cycle. After reversal, maximum VPA plasma concentrations tended to follow the dark phase shift. Correlation was not perfect, nor was the sleep cycle completely reversed since the animals slept less after the phase shift. Possible mechanisms of diurnal plasma level fluctuations and importance of oscillations of this magnitude to clinical drug regimens are discussed.