The
experimental hepatic cirrhosis was induced either by bile duct
ligation (BDL) or by pretreatment with
dimethylnitrosamine (DMNA). The pharmacokinetics of
theophylline were studied after a single intravenous or a single
oral administration. Using the ultrafiltration method,
protein-
drug binding experiments were also carried out. The
bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The
albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of
theophylline in both
hepatic cirrhosis groups significantly decreased and the terminal half-life (t(1/2)) in the cirrhotic rats was increased about two-fold after intravenous and
oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67+/-4.85%) decreased about four-folds, but in DMNA (73.00+/-9.85%) similar result, was observed as compared with the control. Increased free fraction of
theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of
theophylline was mainly due to decreased intrinsic clearance of
theophylline in the liver. The absolute bioavailability of
theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in
Sham operated and Control, 72.8% in DMNA). These results suggest that in the
experimental hepatic cirrhosis model, administration route does not affect the disposition of
theophylline.