Valproate causes metabolic disturbance in normal man

Area of Science:

• Biochemistry
• Pharmacology
• Hepatology

Background:

• Valproate is a crucial anticonvulsant medication.
• It is rarely linked to severe, fatal liver toxicity (hepatotoxicity).
• Prior studies in rats indicated valproate disrupts metabolic processes and lowers blood glucose and ketone levels.

Purpose of the Study:

• To investigate the effects of valproate on human intermediary metabolism.
• To explore the potential link between valproate's metabolic actions and its hepatotoxicity.

Main Methods:

• Oral administration of 1 gram of valproate to fasted healthy humans.
• Intravenous administration of 400 mg of valproate.
• Measurement of blood concentrations of key metabolites including ketone bodies, lactate, pyruvate, alanine, and glycerol.

Main Results:

• Oral valproate caused a 78% decrease in 3-hydroxybutyrate and a 60% decrease in total ketones.
• Significant increases in lactate, pyruvate, alanine, and glycerol concentrations were observed.
• Similar metabolic alterations were noted following intravenous valproate administration.

Conclusions:

• Valproate markedly impacts intermediary metabolism in humans, particularly within the liver.
• These observed metabolic disturbances are likely associated with the mechanism underlying valproate-induced hepatotoxicity.