| Background:First- pass effects is an important factor affecting the bioavailability of drug.When distinguishing the effects of the intestinal extraction of drugs from that of the liver on bioavailability,it needs to administer drug not only orally and from peripheral vein,but also from portal vein,so it is necessary to develop intestinal and vascular access port(ⅣAP) animal model for investigating pharmacokinetics such as regiospecific intestinal absorption and hepatic elimination.Rabeprazole is a new substituted benzimidazole proton pump inhibitor,and the absolute bioavailability was 51.8%in humans,so it needs to clarify the effects of hepatic and intestinal first pass effects on bioavailability of rabeprazole,and to study the enzymes and transporters mechanisms may contribute to its poor oral bioavailability.Helicobacter pylori(Hp) is directly related to acid- related diseases such as peptic ulcer and chronic active gastritis, so rabeprazole usually combined with amoxicillin,clarithromycin and(or) levofloxacin to eradicate it.But these antibiotics may influence the therapeutic effects of rabeprazole,so it is also necessary to study the effects of these antibiotics on pharmacokinetics of rabeprazole.Objective:To develop the Intestinal and Vascular Access Port(ⅣAP) Model for investigating effects of regiospecific intestinal absorption and hepatic elimination on bioavailability and its related mechanisms in rabbits.And to study hepatic and intestinal first pass metabolism of rabeprazole.Furthermore,to study the effect of amoxicillin, clarithromycin and levofloxacin on pharmacokinetics on rabeprazole. Methods:(1) The development of Intestinal and Vascular Access Port(ⅣAP) model: Epidural catheter was inserted from the gastroduodenal vein to portal vein in 16 rabbits.Meanwhile,silastic catheters were placed in the duodenum,10cm from the pylorus,The catheters were tunneled out of the abdomen and attached to separate subcutaneous access ports along the spine,and visualizated after recovery.Rabeprazole was given from duodenum,portal vein and peripheral vein at a dose of 6mg/kg separately to authenticate the model.(2) The bioavailability and hepatic and intestinal first-pass effects of rabeprazole: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.Serial blood samples were collected at various time-points,and plasma drug concentration was analyzed by a high-performance liquid chromatography fluorescence method.Then evaluate pharmacokinetic parameters and caculate absolute bioavailability and hepatic and intestinal extraction ratios.The rabbits were reused once every 1 week.(3) The effect of amoxicillin,clarithromycin and levofloxacin on pharmacokinetics of rabeprazole:Silastic catheters were placed in the duodenum in 6 rabbits firstly,after their recovery,rabeprazole(6mg/kg), rabeprazole(6mg/kg) and amoxicillin(120mg/kg),rabeprazole(6mg/kg) and clarithromycin(60mg/kg),rabeprazole(6mg/kg) and levofloxacin(30mg/kg), rabeprazole(6mg/kg),amoxicillin(120mg/kg) and clarithromycin(60mg/kg) were administered from duodenum for 7 days consecutively to rabbits respectively.And the plasma drug concentration was also analyzed by HPLC method,then to evaluate pharmacokinetic parameters.Results:(1) Two catheters were all implanted in 15 rabbits successfully except one rabbit that died from the anesthetic accident.The rabbits' physiological functions recovered quickly.But the portal vein catheters in two rabbits and duodenum catheters in three rabbits were blocked in two weeks separately after surgery.All the other catheters were maintained patency over one month.Fluoroscopic visualization of intestinal and portal venous catheters indicated that the two catheters were in right position,and gastrointestinal motility was not affected.The oral bioavailability of rabeprazole at a dose of 6mg/kg was 7.9%,the hepatic and intestinal extraction ratio was 78.4%and 63.6%respectively.(2) The pharmacokinetic parameters AUC(0-t),AUC(0-∞)and Cmax increased significantly with increasing doses at intravenous, intraportal and intraduodenal administration respectively(P＜0.05),There were no differences in elimination half-life at any doses in intravenous,intraportal and intraduodenal administration respectively(P＞0.05).But the clearance decreased significantly with increasing doses(P＜0.05).The absolute bioavailability of rabeprazole after intraduodenal administration was 7.4%and 8.3%at the doses of 1.5mg/kg and 3mg/kg respectively;The hepatic extraction ratios was 84.8%and 81.2%,and the intestinal extraction ratios was 51.2%and 56%at the doses of 1.5 and 3mg/kg, respectively.(3)The pharmacokinetic parameters AUC(0-∞)(mg/L*h) were 0.067±0.023,0.053±0.039,0.084±0.054,0.087±0.063,0.065±0.047;T1/2z(h) were 0.462±0.197,0.372±0.11,0.475±0.214,0.599±0.453,0.611±0.385;Tmax(h)were 0.045±0.013,0.075±0.027,0.067±0.026,0.117±0.068,0.107±0.054;CLz/F(L/h/kg) were 326.907±102.83,591.255±401.391,204.249±165.779,345.537±433.892,388.14±144.93;Cmax(mg/L) were 0.313±0.155,0.193±0.192,0.388±0.459,0.285±0.259,0.18±0.092 after rabeprazole,rabeprazole and amoxicillin,rabeprazole and clarithromycin,rabeprazole and levofloxacin,rabeprazole,amoxicillin and clarithromycin administration respectively,but there were no significant differences(P＞0.05) between these parameters.Conclusion:(1) TheⅣAP rabbit model was developed successfully,and it is an ideal pharmacokinetic experimental animal model for investigating intestinal and hepatic extraction of drugs.(2) The AUC(0-t),AUC(0-∞) and Cmax were dose-dependent at intravenous,intraportal and intraduodenal administration in rabbits.(3)The bioavailability of rabeprazole was low at the intraduodenal administration,and was not dose-dependent.The major reason could be that rabeprazole undergoes considerable hepatic and intestinal first-pass effects.(4) Amoxicillin,clarithromycin and levofloxacin have no significant effects on pharmacokinetics of rabeprazole in rabbits.
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