奥美拉唑与雷贝拉唑大鼠肠道首过代谢及机制分析-analysis of intestinal first pass metabolism and its mechanism between omeprazole and rabeprazole in rats.docx

The blood concentrations of omeprazole or rabeprazole were measured by the high-performance liquid chromatography. Extraction ratios in the liver and intestinal tract were determined from the area under the plasma concentration-time curve (AUC).The roles of intestinal efflux by means of P-gp and/or metabolism by CYP3A on the first pass intestinal extraction of omeprazole or rabepzole were differentiated by using ketconazole (an inhibitor of CYP3A) or verapamil(a P-gp inhibitor). Omeprazole or rabepzole was administered by id, ipv or iv to rats alone or 30 min after the id -1 administration of ketoconazole(60mg·kg -1 ) or verapamil(9mg·kg  ), respectively.In  another separated experiment, 30 rats were divided into five groups randomly as omeprazle, rabeprazole, verapamil, dexamethasone and control group, respectively. Drugs (omeprazle, rabeprazole, verapamil and dexamethasone) were given to rats by intragastric administration once a day for 7 days. The control group was given the same dose of saline. On d8, rats were sacrificed, everted sac of jejunum, ileum and colon were prepared quicly and put into Krebs-Ringers solution given with 95%O2 and 5%CO2, 1mL rhodamine 123(5µg·mL) was injected in the serosa side and 500µL samples was obtained from the mucosa side very 10min for 90mins. The activity of P-gp of segments of rat intestine was determined by the secretion of rhodamine 123 using everted sac of jejunum, ileum and colon respectively. Expression of P-gp in jejunum, ileum and colon of rat were immunohistochemistry assays. Results: In IVAP rat model, pharmacokinetic parameters of AUC and Cmax of omeprazole were increased propotionally after id, ipv, and iv administration at various doses. After id administration of various doses, all reached peak concentration within 15mins, and unchanged omeprazole in the whole gastrointestinal were 0.01~0.05% of the given dose, indicating rhat omeprazole can be absorbed rapidly and completely in -1 rats. The bioavailabi