The aim of this study is to report the pharmacokinetics of
omeprazole after intravenous (20 mg/kg) and oral (40 mg/kg) administration to rats with
liver cirrhosis induced by
dimethylnitrosamine (cirrhotic rats) with respect to CYP
isozyme changes. The expressions of
CYP1A2 and 3A1 decreased in cirrhotic rats and
omeprazole is reported to be mainly metabolized via
CYP1A1/2, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, the pharmacokinetics of
omeprazole could be changed in cirrhotic rats. After
intravenous administration to cirrhotic rats, the AUC (1180 microg min/ml versus 474 microg min/ml) and CL(NR) (17.4 ml/min/kg versus 42.3 ml/min/kg) of
omeprazole were significantly greater and slower, respectively, than the controls. This could be due to decrease in the expressions of
CYP1A2 and 3A1 in cirrhotic rats. The significantly slower CL(NR) could be supported by significantly slower in vitro CL(int) for the disappearance of
omeprazole from hepatic microsomal study (0.102 ml/min/mg
protein versus 0.144 ml/min/mg
protein) and slower hepatic blood flow rate in cirrhotic rats. After
oral administration to cirrhotic rats, the AUC difference was considerably greater (451% versus 149%) than that after
intravenous administration, possibly due to decrease in intestinal first-pass effect of
omeprazole in addition to decrease in hepatic metabolism of
omeprazole in cirrhotic rats.