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 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.
Lee
Dae Y
DY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Inchul
I
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A; D004128:Dimethylnitrosamine; D007275:Injections, Intravenous; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000897:Anti-Ulcer Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole; D004128:Dimethylnitrosamine