Trimethadione as a model drug for the evaluation of hepatic drug-metabolizing capacity in normal and alpha-naphthylisothiocyanate-intoxicated rats.
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 in rats pretreated with different dose levels of alpha-naphthylisothiocyanate (ANIT) was investigated. Pretreatment of rats with different dose levels of ANIT resulted in a prolongation of TMO half-life, an increase of the area under the curve (AUC), a decrease of clearance (CL) and a decrease of the apparent volume of distribution (Vd). At any dose of ANIT used, there was a good correlation between the ratio of DMO to TMO in plasma and activities of hepatic cytochrome P-450-dependent drug-metabolizing enzymes, such as cytochrome P-450 and cytochrome b5 contents and aminopyrine N-demethylase, TMO N-demethylase and aniline hydroxylase. These results, together with the previous findings, indicate that determination of the plasma levels of TMO and DMO might be a useful index of drug-metabolizing capacity of the liver.
D015058:1-Naphthylisothiocyanate / Q000506:poisoning*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010080:Oxazoles / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013861:Thiocyanates / Q000506:poisoning*; D014293:Trimethadione / Q000378:metabolism*
D010080:Oxazoles; D013861:Thiocyanates; D015058:1-Naphthylisothiocyanate; D014293:Trimethadione