Simplified approach for evaluation of hepatic drug-oxidizing capacity with a simultaneous measurement of caffeine and its primary demethylated metabolites in carbon tetrachloride-intoxicated rats.

1. Prediction of hepatic injury from changes in blood concentrations of caffeine (CA) and its three primary metabolites (theobromine: TB; paraxanthine: PX; theophylline; TP) after CA administration has been studied in carbon tetrachloride (CCl4)-intoxicated rats. 2. The plasma half-life (t1/2) of CA (10 mg/kg, oral) was increased, and total body clearance (CL) decreased, in CCl4-treated rats; the apparent volume of distribution (Vd) was relatively unchanged. 3. The ratios of CA to the three metabolites (TB/CA, PX/CA, TP/CA) were significantly decreased compared to those of controls. 4. There were good correlations between the ratios of TB/CA, PX/CA, and TP/CA and CL of CA (TB/CA; r = 0.944 at 1 h, r = 0.942 at 2 h: PX/CA; r = 0.974 at 1 h, r = 0.923 at 2 h: TP/CA; r = 0.866 at 1 h, r = 0.962 at 2 h). 5. Results indicate that it is possible to evaluate hepatic drug-oxidizing capacity by measuring the ratio of CA to its metabolites, using single blood sampling 1 or 2 h after CA administration in CCl4-intoxicated rats.