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.
Tanaka
E
E
Institute of Community Medicine, University of Tsukuba, Japan.
Ishikawa
A
A
Yamamoto
Y
Y
Uchida
E
E
Kobayashi
S
S
Yasuhara
H
H
Misawa
S
S
D000284:Administration, Oral; D000818:Animals; D002110:Caffeine / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D002252:Carbon Tetrachloride Poisoning / Q000097:blood / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D005069:Evaluation Studies as Topic; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism*; D008297:Male; D008745:Methylation; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D002110:Caffeine