PHARMACOKINETICS OF THEOPHYLLINE - EFFECTS OF HEPATIC-FIBROSIS IN RATS INDUCED BY BILE-DUCT LIGATION

This experiment was performed to evaluate the usefulness of an experim ental 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 wa s characterized by measurement of the aminoterminal procollagen type I II peptide (PIIINP) level in serum, total collagen content in liver an d light microscopic histology. Four weeks after bile duct ligation the re was an increase in total collagen content of the liver to 430% of t he initial values, accompanied by an increase of serum-PIIINP (385%). Secondly, we examined the pharmacokinetics of theophylline in the fibr otic rat induced by bile duct ligation. An i.v. dose of 8 mg of theoph ylline per kg of body weight was administered, and the levels of theop hylline in serum were assayed by high performance liquid chromatograph y. The area under the serum concentration-time curve of theophylline w as increased significantly in fibrotic rats compared with that of the control, and the total clearance of drug in fibrotic rats was low, ave raging 22.6 mg/kg/h vs. 36.1 and 60.9 ml/kg/h in the control and the n ormal rat, respectively. However, the value of distribution during the beta-phase was not significantly affected by experimental liver fibro sis.