ABSTRACT
The pharmacokinetics of diazepam in normal rats and in rats pretreated with carbon tetrachloride to induce hepatic cirrhosis (cirrhotic rats) was studied after intravenous and oral administration of the drug (4 mg/kg). Animals pretreated with this hepatotoxic agent showed a significant prolongation in the half-life of diazepam in plasma that is due more to an increase in volume of distribution rather than to a decrease in clearance. This study confirmed that diazepam was highly extracted by the rat liver and was not affected by the hepatotoxic agent, although there probably was a saturation of the activity of the cytochrome P450 enzyme when the drug was administered orally. Diazepam binds to plasma proteins to a high degree in both normal and cirrhotic rats; however, in the latter, a significant increase in the fraction of unbound drug in plasma was observed. Pretreatment of rats with carbon tetrachloride did not produce any change either in the distribution of diazepam into erythrocytes or in the disposition of the metabolite desmethyldiazepam.
Subject(s)
Carbon Tetrachloride , Diazepam/pharmacokinetics , Liver Diseases/metabolism , Liver/metabolism , Administration, Oral , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Blood Proteins/metabolism , Chemical and Drug Induced Liver Injury , Diazepam/blood , Disease Models, Animal , Injections, Intravenous , Liver/enzymology , Liver Diseases/enzymology , Male , Protein Binding , Rats , Rats, WistarABSTRACT
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.
