THE DISPOSITION OF VALPROYL GLYCINAMIDE AND VALPROYL GLYCINE IN RATS

Purpose. To investigate the disposition of valproyl glycinamide and va lproyl glycine in rats and to compare it with that of valproic acid (V PA) and valpromide which were studied previously. Methods. The study w as carried out by monitoring the brain and liver levels of valproyl gl ycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds. Results. The following PK paramet ers were obtained for valproyl glycinamide and valproyl glycine, respe ctively: clearance, 7.1 and 16 ml/min/kg; volume of distribution (Vss) , 0.78 and 0.41 l/kg; half-life, 1.1 and 0.37 h; and mean residence ti me, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The r atios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively. Conclusions, Valproyl glycina mide distributes better in the brain than VPA, a fact which may contri bute to its better anticonvulsant activity. Valproyl glycine was barel y distributed in the brain, a fact which may explain its lack of antic onvulsant activity. In addition to the liver, the brain was found to b e a minor metabolic site of the biotransformation of valproyl glycinam ide to valproyl glycine.