Biotransformation of theophylline in cirrhotic rats induced by biliary obstruction

The object of this work was to study the pharmacokinetic differences and th e cause of these differences in cirrhotic rats induced by biliary obstructi on when aminophylline (8 mg/kg as theophylline, i.v.) was administered. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dime thyluric acid from theophylline in microsomes and the changes in the activi ty of drug metabolizing enzymes, which are suggested to be involved in theo phylline metabolism, were determined. In cirrhotic rats, the systemic clear ance of theophylline was reduced to 30% of the control value while AUC (are a under the plasma concentration-time curve) and (t(1/2))(beta) were increa sed 1.3 fold and 3.5 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to 30% of the control value in microsomes of cirrhotic r at liver. In cirrhotic rat liver, activities of aniline hydroxylase (CYP2E1 related), erythromycin-N-demethylase (CYP3A related), and methoxyresorufin -O-demethylase (CYP1A2 related), which were reported to be related with the ophylline metabolism, were decreased to 67%, 53%, and 76% that of normal ra t liver, respectively. From the results, it can be concluded that in cirrho tic rats induced by biliary obstruction, the total body clearance of theoph ylline is markedly reduced and it may be due to decreased activity of drug metabolizing enzymes in liver.