Simplified Test For Determination Of Drug-Oxidizing Capacity In Rats With Chemical-Induced Liver-Injury Using Caffeine And Trimethadione As Model-Drugs

We examined the possibility of predicting the extent of hepatic drug-oxidizing capacity by determination of caffeine, trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), alpha-naphthylisothiocyanate (ANIT: 40 mg/kg), or D-galactosamine (GalN: 400 mg/kg), the half-life (t1/2) of caffeine and trimethadione was significantly (P < 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P < 0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and trimethadione showed a strong correlations (r = 0.99, P < 0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/trimethadione after 1, 2, and 4 hr of trimethadione administration (r = 0.93, P < 0.01; r = 0.97, P < 0.01 and r = 0.97, P < 0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P < 0.01) with the ratio of theobromine/caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration. These findings indicate that the hepatic drug-oxidizing capacity can be evaluated by measuring the plasma concentration ratios of caffeine or trimethadione to their metabolites using single blood sampling within a short time (1 or 2 hr) after administration of caffeine or trimethadione to rats with chemically induced liver injuries.