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© 1986 Oxford University Press

research-article

Pharmacologic Evaluation of Various Metabolites and Analogs of Valproic Acid: Teratogenic Potencies in Mice

HEINZ NAU*,1 and WOLFGANG LÖSCHER{dagger}

*Institute of Toxicology and Embryopharmacology, School of Medicine {dagger}Laborator of Pharmacology and Toxicology, School of Veterinary Medicine, Free University Berlin Federal Republic of Germany

Pharmacologic Evaluation of Various Metabolites and Analogs of Valproic Acid: Teratogenic Potencies in Mice. NAU, H., AND LÖSCHER, W. (1986). Fundam. Appl. Toxicol. 6, 669–676. A number of metabolites of the anticonvulsant drug vaiproic acid (VPA) as well as related substances were tested in regard to their teratogenicity in the mouse following single sc injections of 600 mg/kg on Day 8 of gestation. VPA was highly teratogenic at this dose level and over 60% of live fetuses had neural tube defects (exencephaly). Homologous compounds with shorter or longer alkyl chains were less teratogenic. Substitution of the {alpha}-H atoms in related branched carboxylic acids by methyl or ethyl groups abolished the teratogenic response. Introduction of a double bond in the {omega}-position of VPA (4 did not change the teratogenicity of VPA, while a {omega}-2 double bond (2-en-VPA) abolished teratogenicity. The other VPA metabolites tested as well as two straight-chain acids (n-octanoic acid and 4-pentenoic acid) and the two clinically used substances valpromide (valproic acid amide) and ethosuximide did not induce neural tube defects, although some of them induced slightly increased resorption rates and fetal weight retardation. The serum protein binding capacities of the various compounds did not correlate with the teratogenic response. Also the concentrations reached in the gestational material did not predict the teratogenicity of the substances tested. Our results indicate that the teratogenicity of the class of compounds studied represents a more specific effect than the anticonvulsant activity which could lead to the devel opment of alternative antiepileptic drugs with low embryotoxic potential.


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