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 less than 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P less than 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 less than 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 less than 0.01; r = 0.97, P less than 0.01 and r = 0.97, P less than 0.01 respectively). Besides, total body clearance of
caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P less than 0.01) with the ratio of
theobromine/
caffeine,
paraxanthine/
caffeine and
theophylline/
caffeine after 1, 2 and 4 hr) of
caffeine administration.(ABSTRACT TRUNCATED AT 250 WORDS)