The Effects Of CYP2C19 And IL-1 Genotypes On Proton Pump Inhibitors In Peptic Ulcer Diseases And The Study On Hepatic And Intestinal First-Pass Effects Of Rabeprazole

Background and objective: Proton pump inhibitors (PPIs) are now the most important drugs for acid-related diseases. PPIs together with clarithromycin and amoxicillin/or metronidazole has been considered as the standard first-line regimen for eradication of Helicobecter pylori(H. pylori). Even with the currently most effective treatment regimens, only a little more than 80% of patients show eradication of H. pylori. The host genetic background should be considered to determine the outcome of PPI-based triple therapy. Genetic polymorphism of interleukin (IL)–1βand IL-1 receptor antagonist (IL-1rα) are associated with differences in gastric acid suppression and polymorphisms of cytochrome P (CYP) 2C19 play vital roles in the metabolism of PPIs. Thus, the polymorphisms might affect H. pylori eradication therapy, as antibiotics used in treatment regimens may be acid sensitive. We compared the effects of esomeprazole and rabeprazole vs omeprazole on the ulcer healing and the eradication of H. pylori in relation to CYP2C19, IL-1B and IL-1RN genotypes in Chinese people. Drugs that undergo extensive first-pass elimination often have low and variable bioavailability.The precise role of the hepatic and intestinal first pass effects on bioavailability of rabeprazole has not been clearly defined. Rabeprazole usually combined with amoxicillin and clarithromycin to eradicate H.pylori. So it is also necessary to study the effects of these antibiotics on pharmacokinetics of rabeprazole. We developd the Intestinal and Vascular Access Port (IVAP) Model for studying hepatic and intestinal first pass metabolism of rabeprazole, and to examine whether clarithromycin and amoxicillin would affect rabeprazole pharmacokineticsMethods: 360 consecutive unrelated Chinese Han patients with peptic ulcer disease, who were found to be H. pylori positive were enrolled. The participants were randomly assigned to receive one of the following regimens: 1 g b.i.d. amoxicillin, 500 mg b.i.d. clarithromycin together with either 20 mg b.i.d. omeprazole(OAC group), 10 mg b.i.d rabeprazole(RAC group) or 20mg b.i.d. esomeprazole(EAC group) for 7 days. The maintenance therapy with omeprazole 20 mg b.i.d., esomeprazoleor20 mg b.i.d. or rabeprazole 10 mg b.i.d continued for 3 weeks. A follow-up endoscopy were performed to determine ulcer status at 2 weeks posttreatment. From 1 months after the end of therapy, a 13C urea breath test (13C-UBT) was performed to determine H. pylori status. CYP2C19*2 and *3 , IL1B-511, IL1B-31, IL1B+ 3954 and intron 2 of the IL-1RN genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The cure rate was evaluated by using intention-totreat (ITT) and per protocol (PP) analyses.By developing an in vivo intestinal and vascular access-ported(IVAP) rabbit model, Doses of 0.75, 1.5, 3mg/kg (intravenous); 1.5, 3mg/kg (intraportal) and 1.5, 3, 6mg/kg(intraduodenal) were administered to 6 rabbits respectively. The plasma drug concentration of rabeprazole was analyzed by a high-performance liquid chromatography fluorescence method.Then to evaluate pharmacokinetic parameters and caculate hepatic-intestinal extraction ratios. To study the effects of amoxicillin and clarithromycin on pharmacokinetics of rabeprazole, doses of 6mg/kg rabeprazole,6mg/kg rabeprazole with 120mg/kg amoxicillin, 6mg/kg rabeprazole with 60mg/kg clarithromycin, 6mg/kg rabeprazole with 120mg/kg amoxicillin and 60mg/kg clarithromycin were administered to 6 rabbits duodenum for 7 days respectively. The plasma drug concentration was also analyzed by HPLC method. Results: Of the 360 patients, 340 completed the trial. At ITT and PP analysis, the ulcer healing rates with the rabeprazole ,esomeprazole were significantly (P <0.05) greater than omeprazole at 2 weeks posttreatment. The ulcer healing rate with omeprazole after 2 weeks treatment in CYP2C19 homEM was significantly smaller than in hetEM(P <0.05). The ulcer cure rates at 2 weeks posttreatment did not significantly differ among rabeprazole ,esomeprazole and omeprazole. The improvement ratios of ulcers area after 2 weeks treatment in the rabeprazole , esomeprazole versus omeprazole group were 86.3±9.4%,84.3±13.8% and 79.7±19.9%, respectively (P >0.05). The mean 2-week posttreatment ulcer size value did not significantly differ among the different CYP2C19 genotypes. There were no significant differences among the RAC (85.8%, 89.6%), EAC(88.3%, 91.4%) and OAC(79.2%, 87.2%) groups in the cure rates of H. pylori as determined either by ITT analysis (P >0.05) or PP analysis (P >0.05). There were no significant differences in ITT and PP-based cure rates of H. pylori among the three CYP2C19 genotype groups in each treatment group. However, the H. pylori cure rate of the OAC regimen in the CYP2C19 homEM was significantly lower than that of the RAC and EAC regimens by ITT analysis (P<0.05) or PP analysis (P<0.05). In CYP2C19 homEM genotype, the significant difference in the cure rates of H. pylori was observed between the IL-1B-511 T/T and C/C genotype groups(P <0.05).The AUC and Cmax of rabeprazole were enhanced significantly with increasing doses (P<0.05),There were no differences in elimination half-life at any doses (P>0.05).But the oral clearance decreased significantly with increasing doses(P<0.05). The hepatic extraction ratios of rabeprazole were 84.8% and 81.2%, and the intestinal extraction ratios of rabeprazole were 51.2% and 56% at the doses of 1.5 and 3mg/kg, respectively.To study the effects of amoxicillin and clarithromycin on pharmacokinetics of rabeprazole, the AUC, T1/2z, Tmax and CLz/F values were not difference among rabeprazole group,rabeprazole with amoxicillin group, rabeprazole with clarithromycin group , rabeprazole with amoxicillin and clarithromycin group (P>0.05) .Conclusions: (1)The healing effects of rabeprazole and esomeprazole appear to be independent of the CYP2C19 status, resulting in an earlier ulcer repair compared to that of omeprazole. (2)The rabeprazole- and esomeprazole-based triple regimens have an advantage over omeprazole regimen in the CYP2C19 homEM. (3)The effectiveness of PPI/AC regimen is related to IL-1B-511 genetic polymorphism in the CYP2C19 homEM.(4) The AUC and Cmax of rabeprazole were dose-dependent in rabbits.(5) Rabeprazole underwent considerable hepatic and intestinal first-pass effects in rabbits. (6) Amoxicillin and clarithromycin had no significant effects on pharmacokinetics of rabeprazole in rabbits.