Effects of allyl alcohol and bromobenzene on trimethadione metabolism in the rat.

The relationship between the serum concentration ratio of 5,5-dimethyl-2,4-oxazolidinedione (DMO) to trimethadione (TMO) and the cytochrome P-450-dependent drug-oxidizing enzyme activity in rats pretreated with different dose levels of bromobenzene (BZ) and allyl alcohol (AA) was investigated. Pretreatment of rats with increasing dose levels of BZ and AA resulted in a prolongation of TMO half-life, an increase in the area under the curve (AUC), a decrease in clearance (Cl) and a decrease in the apparent volume of distribution (Vd). At each dose of BZ and AA used, there was a good correlation between DMO/TMO ratios in serum and activities of hepatic cytochrome P-450-dependent drug-oxidizing enzymes, such as cytochrome P-450 content, aminopyrine N-demethylase, TMO N-demethylase and aniline hydroxylase activities. However, the correlation between the serum DMO/TMO ratio and the alcohol dehydrogenase activity in AA treated rats was poor, whereas the activity of this enzyme was not changed in BZ treated rats. These results, together with the previous findings, indicate that determination of the serum levels of TMO and DMO may a useful index of drug-oxidizing capacity of rats with hepatic necrosis specified regions.