INFLUENCE OF FEEDING SCHEDULE ON THE CHRONOPHARMACOLOGICAL ASPECTS OFSODIUM VALPROATE IN MICE

The role of feeding schedule on the chronopharmacological aspects of s odium valproate (valproic acid; VPA) was examined. ICR male mice were housed in a 12-hr light and 12-hr dark cycle (lights on at 0700, off a t 1900) with food and water ad libitum, under a repeated time restrict -ed feeding(feeding time: 0900-1700) for 2 wk, under fasting for 12 hr or under fasting for 12 hr and feeding for 2 hr before the experiment , VPA was used at an i.p. dose of 1200 mg/kg for toxicity, an oral dos e of 600 mg/kg for electroshock seizure threshold and plasma VPA conce ntration, an i.v. dose of 50 mg/kg for pharmacokinetic study and at a rate of 1072.6 mu g/hr for constant-rate administration using an osmot ic minipump, The toxicity, electroshock seizure threshold and VPA conc entration (probably at the absorption phase) were significantly higher in the light and lower in the dark showing rhythmicity. The rhythmici ty in VPA concentration during constant-rate administration was relate d to that of clearance and volume of distribution. The rhythms of elec troshock seizure threshold and VPA absorption were controlled easily b y the temporal manipulation of feeding schedule, but the rhythms of to xicity, clearance and volume of distribution were not. The manipulatio n of the feeding schedule and the choice of the most appropriate time of day for drug administration may help to achieve rational chronother apeutics of some drugs including VPA in certain experimental and clini cal situations.