PHARMACOKINETIC STUDIES OF TRIMETHADIONE AND ITS METABOLITE IN RATS WITH CHEMICAL-INDUCED LIVER INJURY

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A rapid and sensitive gas-liquid chromatographic procedure was developed for the measurements of trimethadione (TMO) and its metabolite, 5,5-dimethyl-2,4-oxazolidinedione (DMO) in plasma. TMO and DMO were extracted from plasma by a micro-extraction method and chromatographed on a 10% Carbowax 6000 column using paramethadione as an internal standard. Recoveries of TMO and DMO ranged from 96 to 104% using a 0.1 ml of plasma. The method is capable of measuring at least 5μg of TMO and DMO per mililiter. After an oral administration of TMO at a dose of 100 mg/kg, mean plasm levels of TMO and DMO in 6 rats reached a peak of 98μg/ml at 0.6 h and 163μg/ml at 8 h and declined with a half-life of 2.2 h and 39.4 h, respectively. After the intravenous administration of TMO at a dose of 100 mg/kg, half-lives of TMO and DMO were 2.5 h and 39.1 h, respectively. Pretreatment of rats with carbon tetrachloride, d-galactosamine and α-naphthyl isothiocyanate, prolonged T_<1/2> and T_<max> of TMO, reduced the K_m value and increased the AUC. These results suggest that plasma levels of TMO and DMO might be useful as an index of drug metabolizing capacity in animal and man.
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