Pharmacokinetic studies of trimethadione and its metabolite in rats with chemical-induced liver injury.

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Abstract
A rapid and sensitive GLC procedure was developed for the measurement 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 96-104% using 0.1 ml plasma. The method was capable of measuring at least 5 .mu.g TMO and DMO per ml. After an oral administration of TMO at a dose of 100 mg/kg, mean plasma levels of TMO and DMO in 6 rats reached a peak of 98 .mu.g/ml [Tmax] at 0.6 h and 163 .mu.g/ml at 8 h, and declined with a half-life [T1/2] of 2.2 and 39.4 h, respectively. After i.v. administration of TMO at a dose of 100 mg/kg, T1/2 of TMO and DMO were 2.5 and 39.1 h, respectively. Pretreatment of rats with CCl4, D-galactosamine and .alpha.-naphthyl isothiocyanate, prolonged T1/2 and Tmax of TMO, reduced the Km value and increased AUC [area under the curve]. Apparently, plasma levels of TMO and DMO might be useful as an index of drug metabolizing capacity in animal and man.