The disposition of valproyl glycinamide and valproyl glycine in rats.
OBJECTIVE
To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously.


METHODS
The study was carried out by monitoring the brain and liver levels of valproyl glycinamide 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 parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: 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 time, 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 ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively.


CONCLUSIONS
Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.
Blotnik
S
S
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Bergman
F
F
Bialer
M
M
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D012015:Reference Standards
D000927:Anticonvulsants; D011355:Prodrugs; C068588:N-(2-propylpentyl)glycinamide; D005998:Glycine