Abstract

The role of feeding schedule on the chronopharmacological aspects of sodium 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 at 1900) with food and water ad libitum, under a repeated time restricted 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 dose of 600 mg/kg for electroshock seizure threshold and plasma VPA concentration, an i.v. dose of 50 mg/kg for pharmacokinetic study and at a rate of 1072.6 micrograms/hr for constant-rate administration using an osmotic minipump. The toxicity, electroshock seizure threshold and VPA concentration (probably at the absorption phase) were significantly higher in the light and lower in the dark showing rhythmicity. The rhythmicity in VPA concentration during constant-rate administration was related to that of clearance and volume of distribution. The rhythms of electroshock seizure threshold and VPA absorption were controlled easily by the temporal manipulation of feeding schedule, but the rhythms of toxicity, clearance and volume of distribution were not. The manipulation of the feeding schedule and the choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of some drugs including VPA in certain experimental and clinical situations.