Demethylation of trimethadione and metharbital by rat liver microsomal enzymes: Substrate concentration-yield relationships and competition between substrates

A study has been made of the relationship between substrate concentration and yield and of competition between substances in the demethylation of trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione) and metharbital (5,5-diethyl-1-methyl barbituric acid) by microsomal enzymes of rat liver. The syntheses of trimethadione- 14C and metharbital- 14C for use as substrates are described. Trimethadione has a much lower affinity for the demethylating enzyme or enzymes than has metharbital. Each of the two substrates has an inhibitory effect on the demethylation of the other. 5,5-Dimethyl-2,4-oxazolidinedione (DMO), the product of dimethylation of trimethadione, has an inhibitory effect about equal to that of trimethadione on the demethylation of metharbital. DMO also inhibits the demethylation of trimethadione.