SERUM-PROTEIN BINDING AND PHARMACOKINETICS OF VALPROATE IN MAN, DOG, RAT AND MOUSE

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  • 1 January 1978
    • journal article
    • research article
    • Vol. 204  (2) , 255-261
Abstract
The serum protein binding of valproate [an antiepileptic agent] (di-n-propylacetate) was determined at therapeutic concentrations by equilibrium dialysis in man (94.8%), dog (78.5%), rat (63.4%) and mouse (11.9%). In dog serum, the binding was independent of the valproate concentration in the range of 5 to about 70 .mu.g/ml, but fell with higher concentrations. The kinetics of valproate was determined in dogs and rats. After i.v. administration, serum concentrations declined biexponentially in both species, the half-life of elimination (T0.5(.beta.) being 1.7 h in dogs and 4.6 h in rats. In comparison with the pharmacokinetics of valproate in man and mouse, the protein binding of valproate is rate-limiting for its clearance by the liver and may be responsible for the striking differences in the half-lives of the drug in different species. Increased drug binding was associated with a decrease in the total clearance and in all species examined, the calculated hepatic extraction ratios (0.009-0.17) were smaller than the free fraction, indicating that valproate fits into the group of drugs with restrictive and liver blood flow independent elimination, i.e., only the unbound drug can be cleared.