Time-Dependent Kinetics III: Diurnal Oscillations in Steady-State Plasma Valproic Acid Levels in Rhesus Monkeys

D Valproic acid was administered by constant rate intravenous infusion to catheterized chaired rhesus monkeys for 8-10 weeks under controlled environmental conditions. Steady-state plasma levels were monitored at 2-hr intervals for 26hr (10am-12 noon on the following day), 1 day/week for 6 weeks. Individual steady-state plasma concentration-time plots exhibited the following characteristics. During Period A (10am-6 pm), plasma levels remained stable or decreased. During Period B (6 pm-6 am), plasma levels increased, reached a maximum, and remained markedly higher than during Period A. The maximum concentrations were 40-140% higher than the observed minimum concentrations. During Period C (6 am-noon), plasma levels tended to decline from the maximum concentrations achieved in Period B. In most cases, plasma concentrations at 10am and 12 noon of the 2nd experimental day fell within 10% of their respective values on the previous day. The mean (±SD) periods obtained by cross-correlation analysis of individual plasma concentration-time plots were 30.7 (±3.7) and 22.8 (±3.6) hr for Animals 903 and 923, respectively. The corresponding mean (±SD) amplitudes were 27.3 (±12.6) and 17.4 (±2.3)%. A circadian rhythm in total body clearance was hypothesized, and its pharmacokinetic implications are discussed.