Time Course of the Demethylation of Trimethadione

A gas chromatographic method for the determination of trimethadione in the serum is described. By this method, the time course of the demethylation of trimethadione to dimethadione, the latter being determined by UV‐spectrophotometry, was followed in mice and dogs. For the demethylation of trimethadione, a half‐life of 45 min. in mice and of 8 hours in dogs was found. The dimethadione formed is excreted extremely slowly: half‐lives were about 30 hours in mice and 50–80 hours in dogs. During chronic treatment dimethadione accumulates: with daily doses of 22–23 mg/kg trimethadione dimethadione concentrations of 175 to 225 μg/ml, while with doses of 64 mg/kg concentrations of about 400 μg/ml were reached in dogs. Under these conditions, unmetabolized trimethadione does not contribute more than 15 per cent maximally to the total anticonvulsant effect of treatment, and the determination of the serum concentrations of dimethadione is therefore considered sufficient for control of therapy.