The inducing and inhibiting effects of sodium valproate in vivo on the biotransformation systems of xenobiotics in isolated rat hepatocytes

Abstract

1. The induction and inhibition of some biotransformation enzymes by valproate have been studied in hepatocytes isolated from rats treated with sodium valproate either i.p. or by subcutaneous implantation of osmotic pumps.

2. When valproate was given i.p., the cytochromes P-450 and b5, and aldrin epoxidase and glutathione S-transferase activities were significantly induced.

3. In contrast, valproate administered by osmotic pumps induced 7-ethoxycoumarin-O-deethylase activity, whereas aldrin expoxidase and glutathione S-transferase activities were significantly inhibited. At a valproate serum concentration of about 100 μg/ml for 2 weeks a significant induction of the cytochromes P-450 and b5 was observed.

4. Since there is a large difference between the half-lives of valproate in man and rodent, constant-rate delivery of valproate represents a better model for induction studies than i.p. injection.