Biomaterial Database

Metabolism and disposition of trimethadione in pregnant rats. 1979

K K Midha, and H S Buttar, and M Rowe, and I Dupuis

The metabolism and disposition of a suspected human teratogen, trimethadione (TMO), was studied in pregnant rats following administration of the drug at doses of 60 and 240 mg/kg/day during 6 to 15 days of gestion, with a view to understanding the fetotoxicity of the drug. Following the last dose, animals were sacrificed at 6, 12, and 24 hr, and the fetuses were removed by caesarean section. The concentrations of TMO and its N-demethylated metabolite, dimethadione (DMO), were determined by a specific GLC procedure in maternal plasma, urine, brain, and liver, as well as in placenta and whole fetus. The plasma and liver concentrations of TMO and DMO suggested that the parent drug is rapidly converted to DMO. Total 24 hr urinary recoveries of the unchanged drug and the metabolite were 61 and 82% following 240 and 60 mg/kg/day doses of TMO, respectively. The DMO concentrations in brain and all other tissues analyzed were far greater than those of TMO. The fetus to maternal plasma concentration ratios of TMO suggested that the placental transfer of the drug was greater than the clearance from the fetus over the periods examined, whereas the transfer of the metablite seemed to be independent of dose. Furthermore, the rate of decline of DMO in fetus was far slower than that of the placenta and maternal plasma, causing accumulation of DMO in the fetus. The results suggest that the fetotoxic effects produced by TMO when given to pregnant rats could be due to accumulation of DMO in fetus.

UI	MeSH Term	Description	Entries
D010080	Oxazoles	Five-membered heterocyclic ring structures containing an oxygen in the 1-position and a nitrogen in the 3-position, in distinction from ISOXAZOLES where they are at the 1,2 positions.	Oxazole,1,3-Oxazolium-5-Oxides,Munchnones,1,3 Oxazolium 5 Oxides
D011247	Pregnancy	The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH.	Gestation,Pregnancies
D004114	Dimethadione	An anticonvulsant that is the active metabolite of TRIMETHADIONE.	5,5-Dimethyl-2,4-oxazolidinedione,5,5-Dimethyloxazolidine-2,4-dione,Dimethyloxazolidinedione
D004353	Drug Evaluation, Preclinical	Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.	Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D005260	Female		Females
D005333	Fetus	The unborn young of a viviparous mammal, in the postembryonic period, after the major structures have been outlined. In humans, the unborn young from the end of the eighth week after CONCEPTION until BIRTH, as distinguished from the earlier EMBRYO, MAMMALIAN.	Fetal Structures,Fetal Tissue,Fetuses,Mummified Fetus,Retained Fetus,Fetal Structure,Fetal Tissues,Fetus, Mummified,Fetus, Retained,Structure, Fetal,Structures, Fetal,Tissue, Fetal,Tissues, Fetal
D000014	Abnormalities, Drug-Induced	Congenital abnormalities caused by medicinal substances or drugs of abuse given to or taken by the mother, or to which she is inadvertently exposed during the manufacture of such substances. The concept excludes abnormalities resulting from exposure to non-medicinal chemicals in the environment.	Drug-Induced Abnormalities,Abnormalities, Drug Induced,Abnormality, Drug-Induced,Drug Induced Abnormalities,Drug-Induced Abnormality
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013723	Teratogens	An agent that causes the production of physical defects in the developing embryo.	Embryotoxins,Fetotoxins,Teratogen
D014293	Trimethadione	An anticonvulsant effective in absence seizures, but generally reserved for refractory cases because of its toxicity. (From AMA Drug Evaluations Annual, 1994, p378)	Tridione,Trimetin,Troxidone