No abstract

It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague-Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague-Dawley rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U-ARF rats. After intravenous administration of omeprazole (20 mgkg −1 ) to U-ARF rats, the area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 mgminmL), possibly due to the significantly faster non-renal clearance (56.6 vs 41.2 mL min −1 kg −1 ) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U-ARF rats. After oral administration of omeprazole (40 mgkg −1 ) to U-ARF rats, the AUC was also significantly reduced (89.3 vs 235 mg minmL −1 ) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U-ARF rats, in addition to increased hepatic metabolism.

A series of experiments using various inducers and inhibitors of the hepatic microsomal cytochrome P450 (CYP) isozymes were conducted to find CYP isozymes responsible for the metabolism of omeprazole in male Sprague-Dawley rats. Omeprazole, 20 mg/kg, was administered intravenously. In rats pretreated with SKF 525-A (a nonspecific CYP isozyme inhibitor in rats), the time-averaged nonrenal clearance (Cl(nr)) was significantly slower (77.1% decrease) than that in untreated rats. This indicated that omeprazole is metabolized via CYP isozymes in rats. Hence, rats were pretreated with various enzyme inducers and inhibitors. In rats pretreated with 3-methylcholanthrene and dexamethasone (main inducers of CYP1A1/2 and 3A1/2 in rats, respectively), the Cl(nr) values were significantly faster (43.8% and 26.3% increase, respectively). In rats pretreated with troleandomycin and quinine (main inhibitors of CYP3A1/2 and 2D1 in rats, respectively), the Cl(nr) values were significantly slower (20.9% and 12.9% decrease, respectively). However, the Cl(nr) values were not significantly different in rats pretreated with orphenadrine, isoniazid and sulfaphenazole (main inducers of CYP2B1/2 and 2E1, and a main inhibitor of 2C11, respectively, in rats) compared with those of respective control rats. The above data suggested that omeprazole could be mainly metabolized via CYP1A1/2, 3A1/2 and 2D1 in male rats.

Purpose. To investigate the effect of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS) on the pharmacokinetics of omeprazole in rats. It has been reported that omeprazole is primarily metabolized via hepatic CYP1A2, 2D1, and 3A1 in rats. The expression and mRNA levels of hepatic CYP1A2 and 3A1 increases in DMIA and DMIS rats, but the expression of hepatic CYP2D1 does not change in DMIS rats. In addition, the metabolic activities of intestinal CYP3A1/2 decreases in DMIS rats. Thus, it could be expected that the pharmacokinetics of omeprazole would be affected by changes in both DMIA and DMIS. Methods. Omeprazole was administered intravenously (20 mg/kg) and orally (40 mg/kg) to DMIA and DMIS rats and their respective controls. Results. After intravenous administration of omeprazole, the CLNR of the drug was significantly faster in DMIA (52.6 versus 67.4 mL/min/kg) and DMIS (50.2 versus 73.0 mL/min/kg) rats than the respective controls. However, after oral administration of omeprazole, the AUC was comparable between each type of diabetic rat and the respective controls. Conclusions. The significantly faster CLNR of intravenous omeprazole could be due to increased expression and mRNA levels of hepatic CYP1A2 and 3A1 in both types of diabetic rat. The comparable AUC of oral omeprazole could be due to a decrease in the intestinal first-pass effect of omeprazole caused by decreased intestinal CYP3A1/2 in diabetic rats. Following both intravenous and oral administration in DMIA and DMIS rats, the pharmacokinetics of omeprazole were similarly altered.