| Background: It has been widely hypothesized that intestinal apical secretion and/or CYP3A-mediated metabolism may profoundly affect a drug's bioavailability (BA); CYP3A is a major phase I drug metabolizing enzyme that potentially mediates the biotransformation of more than 50% of known drugs with its gene expression levels being 30% and 70% of total cytochromes P450 in human liver and intestine, respectively. P-glycoprotein (P-gp) is thought not only to affect the secretion of a variety of drugs in the small intestine of the body, but it can also affect the metabolism and disposition of drugs. CYP3A and P-gp have wide overlapping substrate specificity and may have synergisitic effects on form the barrier to oral drug absorption. However, the ability to directly assess the potential importance of these two intestinal processes in vivo has represented a major technological challenge with little success being demonstrated to date.Objective: The aim of this study was to evaluate the effects of intestinal and hepatic extraction on the bioavailability of omeprazole and rabeprazole and the possible involvement of cytochromeCYP3Aand P-gp in this process in rats.The second aim of this study was to investigate the effects of consecutive administration of omeprazole or rabeprazole on the intestinal P-gp activity and protein expression in rats.Methods: The current study was performed in intestinal and vascular access ported (IVAP) rats to quantify and differentiate the components of intestinal and hepatic first pass extraction of omeprazole or rabepzole mediated by CYP3A and P-gp. Omeprazole or rabeprazole was administered by intravenous injection (i.v., 1.5–6 mg·kg-1), inrtraportal infusion (ipv, 1.5–6 mg·kg-1) or intraduodenal instillation (id, 3–9 mg·kg-1). 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 administration of ketoconazole(60mg·kg-1) or verapamil(9mg·kg-1), 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 rats. The bioavailability after id administration of 3 and 6 mg·kg-1 of omeprazole was 20.73±2.49% and 22.07±2.92%, respectively. And the EH was 50.00±4.16% and 60.19±1.27%, EI was 58.59±1.54%, 44.41±9.13%, respectively. Pharmacokinetic parameters of AUC and Cmax of rabeprazole were increased propotionally after id, ipv, and iv administration at various doses. After id administration of various doses, all reached peak concentration within 9mins, and unchanged rabeprazole in the whole gastrointestinal were 0.15～0.25% of the given dose, indicating rhat rabeprazol can be absorbed rapidly and completely in rats. The bioavailability after id administration of 3 and 6 mg·kg-1 of rabeprazol was 15.28±2.05% and 27.16±2.47%, respectively. And the EH was16.77±2.85% and 27.79±3.43%, EI was 81.65±2.28%, 62.26±4.69%, respectively. Compared with the control group, the presence of ketoconazole (60 mg·kg-1) or verapamil (9 mg·kg-1) significantly increased AUCand Cmax of id-administered omeprazole or rabeprazle, while it had no significant effect on those of omeprazole or rabeprazle administered by iv ports. Consecutive administration of omeprazole for 7ds significantly inhibited intestinal P-gp activity and protein expression of rat respectively, while consecutive administration of rabeprzole have no siginificant effects on them.Conclusion: Oral omeprazole or rabeprazole undergoes marked intestinal first pass metabolism in rats. Omeprazole has a comparable hepatic and intestinal first pass metabolism in rat, while intestinal metabolism of rabeprazole significant higer than that of in liver. The BA of rabeprazole may increase dose-dependently, while that of omeprazole may not increase with oral dose. CYP3A-mediated metabolism and P-gp mediated effluex are both involve in the intestinal metabolism of omeprazole or rabeprazole.Inhibition of CYP3A and P-gp may marked increase the BA of omeprazole or rabeprazle. Consecutive administration of omeprazole significantly inhibited intestinal P-gp activity and protein expression of rat, while rabeprzole have no siginificant effects on them.
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