Systemic interaction between valproic acid and free fatty acids in rhesus monkeys.

The interaction between valproic acid (VPA) and free fatty acids (FFA) was investigated at a systemic level in eight rhesus monkeys. Intralipid emulsion (I.L.) was infused to increase plasma FFA levels. During I.L. treatment, plasma FFA levels were elevated in all cases (12 cases) with increases ranging from 38 to 525% (median, 102%). Valproate free fraction (fp) was elevated in 11 of 12 cases, with increases ranging between 7 and 100% (median, 18%). A positive correlation between the relative increase in FFA and the corresponding increase in fp of VPA was obtained. Intralipid infusion was associated with changes in the systemic clearance of VPA (an increase in five cases and a decrease in seven cases). The intrinsic clearance (Clint) of VPA was decreased in 9 of 12 cases with decreases ranging from 13 to 78% (median, 22%). Urinary excretion of valproate glucuronide was decreased in three of four monkeys during I.L. treatment. A significant positive correlation (p less than 0.05) between the relative increase in FFA levels and the decrease in Clint of VPA were also observed. The mechanism of interaction between VPA and FFA in rhesus monkey is more complex than a simple protein binding displacement and involves at least one metabolic inhibition component such as glucuronidation.