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This experiment was performed to evaluate the usefulness of an experimental fibrosis model by bile duct ligation as a pharmacokinetic model of a disease state. First, experimental liver fibrosis was produced by bile duct ligation. At 4 weeks postoperation, a fibrotic condition was characterized by measurement of the aminoterminal procollagen type III peptide (PIIINP) level in serum, total collagen content in liver and light microscopic histology. Four weeks after bile duct ligation there was an increase in total collagen content of the liver to 430% of the initial values, accompanied by an increase of serum-PIIINP (385%). Secondly, we examined the pharmacokinetics of theophylline in the fibrotic rat induced by bile duct ligation. An i.v. dose of 8 mg of theophylline per kg of body weight was administered, and the levels of theophylline in serum were assayed by high performance liquid chromatography. The area under the serum concentration-time curve of theophylline was increased significantly in fibrotic rats compared with that of the control, and the total clearance of drug in fibrotic rats was low, averaging 22.6 mg/kg/h vs. 36.1 and 60.9 ml/kg/h in the control and the normal rat, respectively. However, the value of distribution during the beta-phase was not significantly affected by experimental liver fibrosis.

Pharmacokinetics of Theophylline: Effects of Hepatic Fibrosis in Rats Induced by Bile Duct Ligation.