Watanabe K, Furuno K, Eto K, Oishi R, Gomita Y
Department of Hospital Pharmacy, Okayama University Medical School, Japan.
J Pharm Sci. 1994 Aug;83(8):1131-4. doi: 10.1002/jps.2600830812.
To clarify the in vivo first-pass metabolism of omeprazole, the pharmacokinetics were examined after oral, intraduodenal (i.d.), intraportal venous (i.p.v), and intravenous (i.v.) administration at various doses to rats. Extraction ratios in the liver and intestinal tract were determined from the areas under the concentration-time curve (AUC) for i.p.v. and i.v. administration and from those for id and ipv administration, respectively. 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 orally 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 distribution volume of steady state, total clearance, or elimination half-life at any doses. In addition, the AUC value after oral administration (20 mg/kg) in rats acutely intoxicated with CCl4 was 2.4 times larger than that in the control. These findings suggest that omeprazole undergoes 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-dependent increase in bioavailability is a saturation of the first-pass metabolism in the liver.
为阐明奥美拉唑的体内首过代谢情况，对大鼠给予不同剂量的奥美拉唑后，分别经口服、十二指肠内（i.d.）、门静脉内（i.p.v）和静脉内（i.v.）给药，并检测其药代动力学。肝脏和肠道的提取率分别根据门静脉内和静脉内给药的浓度-时间曲线（AUC）以及十二指肠内和门静脉内给药的浓度-时间曲线来确定。假设药物从胃肠道完全吸收，在剂量为2.5、5和10mg/kg时，肝脏和肠道的提取率分别为0.80、0.63和0.59，在剂量为5和10mg/kg时，提取率分别为0.70和0.73。在剂量为10、20和40mg/kg时，口服奥美拉唑的生物利用度分别为6.4%、9.6%和12.6%。在任何剂量下，稳态分布容积、总清除率或消除半衰期均无差异。此外，四氯化碳急性中毒大鼠口服给药（20mg/kg）后的AUC值是对照组的2.4倍。这些研究结果表明，奥美拉唑在肠黏膜和/或肠腔内以及肝脏中均经历首过代谢，并且生物利用度随剂量增加的主要原因是肝脏首过代谢的饱和。
