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

Publisher Website
Google Scholar
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 (Vd) 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.
Keywords