Abstract
Valproate is an important anticonvulsant which is rarely associated with fatal hepatotoxicity. Previous experiments have shown that valproate inhibits several metabolic processes in isolated rat hepatocytes and when administered to starved rats causes a fall in the blood concentrations of glucose and ketone bodies. Since these changes may be related to the hepatotoxicity, the effect of valproate administration on intermediary metabolism in man was studied. One gram of valproate given orally to fasted normal humans caused a 78% fall in the concentration of 3-hydroxybutyrate and a 60% fall in total ketones. Also the concentrations of lactate, pyruvate, alanine and glycerol increased after valproate administration. Similar changes were observed after intravenous administration of 400 mg of valproate. Valproate clearly has a significant effect on intermediary metabolism in the liver and this is probably related to the mechanism of the hepatotoxicity.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Becker C. M., Harris R. A. Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Arch Biochem Biophys. 1983 Jun;223(2):381–392. doi: 10.1016/0003-9861(83)90602-1. [DOI] [PubMed] [Google Scholar]
- Ho R. J., Meng H. C. A simple and ultrasensitive method for determination of free fatty acid by radiochemical assay. Anal Biochem. 1969 Oct 1;31(1):426–436. doi: 10.1016/0003-2697(69)90284-x. [DOI] [PubMed] [Google Scholar]
- Johnston D. G., Blesa-Malpica G., Burrin J. M., Waugh C., Cook D., Orskov H., Alberti K. G. Dopamine blockade inhibits starvation ketosis in man. Clin Endocrinol (Oxf) 1983 Sep;19(3):389–396. doi: 10.1111/j.1365-2265.1983.tb00012.x. [DOI] [PubMed] [Google Scholar]
- Lloyd B., Burrin J., Smythe P., Alberti K. G. Enzymic fluorometric continuous-flow assays for blood glucose, lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem. 1978 Oct;24(10):1724–1729. [PubMed] [Google Scholar]
- Mortensen P. B., Gregersen N., Kølvraa S., Christensen E. The occurrence of C6--C10-dicarboxylic acids in urine from patients and rats treated with dipropylacetate. Biochem Med. 1980 Oct;24(2):153–161. doi: 10.1016/0006-2944(80)90006-x. [DOI] [PubMed] [Google Scholar]
- Thurston J. H., Carroll J. E., Dodson W. E., Hauhart R. E., Tasch V. Chronic valproate administration reduces fasting ketonemia in children. Neurology. 1983 Oct;33(10):1348–1350. doi: 10.1212/wnl.33.10.1348. [DOI] [PubMed] [Google Scholar]
- Turnbull D. M., Bone A. J., Bartlett K., Koundakjian P. P., Sherratt H. S. The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochem Pharmacol. 1983 Jun 15;32(12):1887–1892. doi: 10.1016/0006-2952(83)90054-0. [DOI] [PubMed] [Google Scholar]
- WILLIAMSON D. H., MELLANBY J., KREBS H. A. Enzymic determination of D(-)-beta-hydroxybutyric acid and acetoacetic acid in blood. Biochem J. 1962 Jan;82:90–96. doi: 10.1042/bj0820090. [DOI] [PMC free article] [PubMed] [Google Scholar]