Pharmacokinetics of diazepam in the rat: influence of an experimentally induced hepatic injury.
The aim of this study was to compare the pharmacokinetics of diazepam in normal rats and rats with a carbon tetrachloride-induced hepatic cirrhosis after intravenous and oral administration of the drug (4 mg/Kg). When animals are pretreated with this hepatotoxic agent, a significant prolongation in plasma half-life of diazepam is observed, due more to an increase in volume of distribution rather than to a decrease in clearance. Our findings confirm that diazepam is highly extracted by the liver of the rat. This parameter is not affected by the hepatotoxic agent, but probably there is a saturation of the hepatic enzyme activity when the drug is orally administered at the dose of 4 mg/Kg. Diazepam binds to a high degree to plasma proteins in normal and damaged rats, though in the last case a significant increase in the unbound fraction of drug in plasma is observed. Pretreatment of rats with Cl4C does not produce any change in distribution of diazepam into erythrocytes.
Diaz-Garcia
J M
JM
Dpto. Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Spain.
Oliver-Botana
J
J
Fos Galve
D
D
D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism; D007275:Injections, Intravenous; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D001798:Blood Proteins; D003975:Diazepam