FIRST-PASS METABOLISM OF OMEPRAZOLE IN RATS

To clarify the in vivo first-pass metabolism of omeprazole, the pharma cokinetics wars examined after oral, intraduodenal (id), intraportal v enous (ipv), and intravenous (iv) administration at various doses to r ats. Extraction ratios in the liver and intestinal tract were determin ed from the areas under the concentration-time curve (AUC) for ipv and iv administration and from those for id and ipv administration, respe ctively. Assuming that the drug was absorbed from the gastrointestinal tract completely, the hepatic and intestinal extraction ratios were 0 .80, 0.63, and 0.59 at doses of 2.5, 5, and 10 mg/kg and 0.70 and 0.73 at doses of 5 and 10 mg/kg, respectively. The bioavailability of oral ly administered omeprazole was 6.4, 9.6, and 12.6% at the doses of 10, 20, and 40 mg/kg, respectively. There were no differences in the dist ribution volume of steady state, total clearance, or elimination half- life at any doses. In addition, the AUC value after oral administratio n (20 mg/kg) in rats acutely intoxicated with CCl4 was 2.4 times large r than that in the control. These findings suggest that omeprazole und ergoes a first-pass metabolism in the intestinal mucosa and/or lumen, as well as in the liver, and that the major contribution to the dose-d ependent increase in bioavailability is a saturation of the first-pass metabolism in the liver.