Changes in caffeine, lidocaine and trimethadione metabolism in carbon tetrachloride-intoxicated rats as assessed by a "cocktail" study.
We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)-induced liver injury using a strategy referred to as a "cocktail" study. These 3 probe drugs were simultaneously administered intravenously. The half-lives (t1/2) of caffeine, lidocaine and trimethadione were significantly longer in the CCl4-treated group than in oil-treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4-treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug-oxidizing capacity in liver disease.
Tanaka
E
E
Institute of Community Medicine, University of Tsukuba, Ibaraki-ken, Japan.
Ishikawa
A
A
Misawa
S
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002110:Caffeine / Q000493:pharmacokinetics*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D007275:Injections, Intravenous; D008012:Lidocaine / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014293:Trimethadione / Q000493:pharmacokinetics*
D004338:Drug Combinations; D002110:Caffeine; D008012:Lidocaine; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D014293:Trimethadione