Determination of plasma trimethadione and its metabolite in carbon tetrachloride-intoxicated rat liver: A useful tool for estimation of hepatic drugmetabolizing capacity.

Abstract

1. The relationship between the plasma concentration ratio of 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) to trimethadione (TMO) and cytochrome P-450 dependent drug-metabolizing enzyme activities after administration of TMO to rats pretreated with different dose levels of carbon tetrachloride (CCl₄) was investigated. 2. Pretreatment of rats with different dose levels of CCl₄ resulted in a prolongation of TMO half-life, an increase of the area under the curve (AUC), and a decrease of clearance, but the apparent volume of distribution (V_d) was not significantly decreased. 3. Depending on the extent of liver-injury by CCl₄, there was a good correlation between the ratio of DMO to TMO in plasma and hepatic cytochrome P-450 dependent drug-metabolizing enzyme activities such as cytochrome P-450 content (r=0.796 at 1 h, r=0.849 at 2 h), aminopyrine N-demethylase activity (r=0.877 at 1 h, r=0.905 at 2 h), TMO N-demethylase activity (r=0.876 at 1 h, r=0.928 at 2 h) and aniline hydroxylase activity (r=0.900 at 1 h, r=0.936 at 2 h). 4. These results, together with the previous findings, indicate that determination of the plasma levels of TMO and DMO might be a useful tool as an index of drugmetabolizing capacity of rat livers.