Co-variation in frequency and severity of cardiovascular and skeletal defects in Sprague-Dawley rats after maternal administration of dimethadione, the N-demethylated metabolite of trimethadione.

BACKGROUND: The anticonvulsant trimethadione is a potent inducer of ventricular septation defects, both clinically and in rodents. Teratogenicity requires its N-demethylation to dimethadione, the proximate teratogen. It was previously demonstrated trimethadione only induced membranous ventricular septation defects in rat (Fleeman et al., 2004), and our present goal is to determine whether direct administration of dimethadione increases the incidence and severity of septation defects. METHODS: Pregnant Sprague-Dawley rats were divided into five groups and administered either distilled water (control) or four different regimens of dimethadione. The core treatment was 300 mg/kg dimethadione b.i.d. on gestation day 9, 10 with additional groups given one additional dose of dimethadione 12 hr earlier, 12 hr later or two additional doses 12 hr earlier and later. Caesarian sections occurred on gestation day 21 and fetuses were examined for standard developmental toxicity endpoints. RESULTS: The broadest dosing regimen yielded the highest incidence and the most severe heart and axioskeletal findings with a decrease in mean fetal body weight. The overall incidence of ventricular septation defects was 74%, of which 68% were membranous and 9% muscular. Outflow tract anomalies (17%) were also observed, as were malformations of the axioskeleton (97%), but not of the long bones, and of particular interest was the high incidence of sternoschesis. CONCLUSIONS: Unlike trimethadione, dimethadione induces more serious muscular septation defects that are believed to be more clinically relevant. This, when taken together with the high incidence of total septation anomalies suggests dimethadione is useful for the study of chemically induced ventricular septation defects.

A simplified approach for evaluation of hepatic drug-oxidizing activity with a simultaneous determination of caffeine and trimethadione and their demethylated metabolites in rats with a selective cytochrome P-450 inducer.

We determined the blood concentrations of caffeine (CA) and its three primary dimethylxanthine metabolites: theobromine (TB), paraxanthine (PX), and theophylline (TP), and trimethadione (TMO) and its demethylated metabolite dimethadione (DMO) after the simultaneous administration of CA (10 mg kg-1) and TMO (4 mg kg-1) to rats pretreated with phenobarbital (PB:40 and 80 mg kg-1 i.p. daily for 3 days) and 3-methylcholanthrene (MC: 10 and 20 mg kg-1 i.p. daily for 2 days). After the oral administration of CA and TMO, the PB-pretreated rats showed a significant increase in TMO metabolism, whereas the CA metabolism was greatly accelerated in rats pretreated with MC. In five pretreated groups, there were correlations which were determined 1 h after the administration of CA and TMO, between the plasma half-life (t1/2) of CA and the TB/CA, PX/CA, and TP/CA ratios. The coefficients of correlation (r) ranged from -0.881 to -0.908, and the coefficients of correlation between the CL of CA and the TB/CA, PX/CA, and TP/CA ratios ranged from 0.959 to 0.989. There were high correlations between the t1/2 of TMO and the DMO/TMO ratio at 1 h after administration with r = -0.966, and between the CL of TMO and the DMO/TMO ratio with r = 0.971. The above results suggest that one blood sampling after the simultaneous administration of CA and TMO enables prediction of the degree of each hepatic drug-oxidizing activity because the P-450 isozymes involved in metabolism of CA and TMO are different.