Pharmacokinetics of omeprazole after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine

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 orneprazole is reported to be mainly metabolized via CYP1A1/2, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, the pharmacokinetics of orneprazole could be changed in cirrhotic rats. After intravenous administration to cirrhotic rats, the AUC (1180 mu g min/ml versus 474 mu g min/ml) and CLNR (17.4 ml/min/kg versus 42.3 ml/min/kg) of orneprazole were significantly greater and slower, respectively, than the controls. This could be due to decrease in the expressions of CYPIA2 and 3A1 in cirrhotic rats. The significantly slower CLNR could be supported by significantly slower in vitro CLint for the disappearance of orneprazole 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 orneprazole in cirrhotic rats. (c) 2006 Elsevier B.V. All rights reserved.