Serum aminotransferase activity as a predictor of clearance of drugs metabolized by CYP isoforms in rats with acute hepatic failure induced by carbon tetrachloride.
The values of serum aminotransferase activity (AST) in untreated rats and rats with acute hepatic failure at 24h after an oral administration of CCl(4) (0.5 ml/kg) were 85+/-9 IU/l and 4260+/-620 IU/l (mean+/-S.D., n=6), respectively. The values of total clearance (CL(tot)) after intravenous administration of caffeine, tolbutamide, chlorzoxazone or lidocaine (as probe drugs for various CYP isoforms) to CCl(4)-treated rats were decreased to about 1/8, 1/3, 1/3 or 1/2 compared with those in untreated rats. Good correlations were observed between mRNA expression and enzyme activity of CYP2C11, CYP2E1, CYP3A2 and CYP1A2 in livers of rats given various doses of CCl(4). There was also a good negative correlation between serum AST activity and hepatic enzyme activity of each CYP. The serum AST activities corresponding to a 50% decrease of CYP2C 11, CYP2E1, CYP3A2 and CYP1A2 activities were about 710, 780, 1030 and 1300 IU/l, respectively. In conclusion, when the serum AST value in CCl(4)-treated rats reached about 4000 IU/l, the hepatic CYP activities were one-tenth or less of the control, although the degree of decrease of the CL(tot) values varied markedly. Nevertheless, the AST value appears to be a promising candidate for an indicator to predict appropriate dose modification of drugs for patients with acute hepatic failure.
Yokogawa
Koichi
K
Department of Hospital Pharmacy School of Medicine, Kanazawa University, 13-1, Takara-machi, Kanazawa 920-8641, Japan. miyaken@pharmacy.m.kanazawa-u.ac.jp
Watanabe
Mao
M
Takeshita
Harunori
H
Nomura
Masaaki
M
Mano
Yasunari
Y
Miyamoto
Ken-ichi
K
D000818:Animals; D019540:Area Under Curve; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000378:metabolism; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006207:Half-Life; D007527:Isoenzymes / Q000378:metabolism*; D008012:Lidocaine / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics; D000637:Transaminases / Q000097:blood*
D007527:Isoenzymes; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D008012:Lidocaine; D000637:Transaminases; D002753:Chlorzoxazone