A method for estimation of hepatic drug-metabolizing capacity: determination of concentration of trimethadione and its metabolite in human serum.

There have been significant correlations between serum concentration ratios of 5,5-dimethyl-2,4-oxazolidinedione (Dimethadione, DMO)/trimethadione (TMO) after administration of TMO and hepatic microsomal cytochrome P-450 contents in rats with various treatments (CCl4 or phenobarbital). The pharmacokinetics of TMO and DMO, and the serum concentration ratio of DMO/TMO have been investigated in healthy volunteers after oral administration of 1 mg/kg (N = 4), 2 mg/kg (N = 6) and 4 mg/kg (N = 6) TMO, respectively. TMO and DMO concentrations in serum were determined by a gas-liquid chromatographic method. Serum disappearance of TMO was described by one compartment model. The T1/2, Kel, Vd and C1 of TMO and of DMO were shown to have almost the same values in 2 mg/kg or 4 mg/kg TMO administration. Correlation coefficient between DMO/TMO ratio in serum and time course after 1 mg/kg, 2 mg/kg and 4 mg/kg TMO administration was found to be r = 0.958, r = 0.924 and r = 0.938, respectively. These results indicate that the serum concentration ratio of DMO/TMO, especially at 2 or 4 h after 4 mg/kg TMO administration orally, may be an index of hepatic drug-metabolizing capacity in human serum as well as in rats.