실험적 간질환에서 Theophylline의 체내동태 = Pharmacokinetics of Theophylline in Experimental Hepatic Diseases

다국어 초록 (Multilingual Abstract)

This study was carried out to investigate the mechanism of altered drug elimination in hepatic diseases using theophylline as an example of a drug that is extensively metabolized by the liver and have a narrow therapeutic range. Firstly, we established the experimental hepatic cirrhosis model in rats. Three kinds of method were used to induce hepatic cirrhosis; (1) bile duct ligation/scission; (2) N, N- dimethylnitrosamine; (3) carbon tetrachloride. Secondly, the pharmacokinetics of theophyl1ine(8㎎/㎏, as theophyl1ine, i.v.) was studied in three kinds of experimental hepatic cirrhosis model. And the concentration of 1,3-dimethyluric acid (major metabolite of theophylline) in plasma of the cirrhotic rats was determined. Thirdly, the activities of the hepatic microsomal aniline hydroxylase and ethoxyresorufin-O-deethylase were determined. And as an in vitro test, theophylline metabolites were determined from the extract from the incubation mixture of the theophylline and hepatic microsomal system. The hepatic enzyme activity was correlated with the content of the metabolites formed after the incubation.
The results were as follows;
1) The serum ALT, AST, ALP, total bilirubin levels and hydroxyproline content in liver of the experimental hepatic cirrhosis model were significantly elevated and the histological aspects of the liver appeared as cirrhosis.
2) In the experimental hepatic cirrhosis, the values of AUC and t_½ were significantly increased and the Cl_8 and K_10 was significantly reduced. The 1,3-dimethyluric acid was not detected in cirrhotic rats.
3) In microsomal incubation, 1,3-dimethyluric acid formation was decreased in cirrhotic rats. And the decrease in 1,3-dimethyluric acid formation in vitro was accompanied by the decline in aniline hydroxylase(P450 2E1 related) activity in experimental hepatic cirrhosis.
The results indicate that in experimental hepatic cirrhosis, altered theophylline elimination is mainly due to decreased hepatic drug metabolizing activity and the biotransformation of theophylline to 1,3-dimethyluric acid may be affected by cytochrome P4502E1 .