The Study Of Intestinal Absorption And Biodistribution In Vivo Of Proton Pump Inhibitors

At present,the use of oral proton pump inhibitors?PPIs?to suppress excessive gastric acid secretion is one of the main methods for treating gastrointestinal diseases related to them.However,PPI is extremely unstable in the acidic environment of the gastrointestinal tract,and it is difficult to maintain its prototype molecular structure.So far,there have been few research data on the absorption behavior parameters of oral PPI in vivo.In this research,we first studied the degradation rate of four representative second-generation PPIs?including ilaprazole,ilaprazole sodium,rabeprazole sodium,and esomeprazole magnesium?over time under different pH conditions.Then an improved in situ unidirectional intestinal perfusion model of rats was established,so that PPI can maintain high enough stability under appropriate temperature and time conditions.Three concentrations of drug-phenol red solution?5?g/mL,20?g/mL and40?g/mL?were used to respectively do unidirectional perfusion the duodenum,jejunum,ileum and colon of rats with flow rate?0.2 mL/min?.Using high-performance liquid chromatography?HPLC?and liquid-phase secondary mass spectrometry?LC-MS/MS?analysis methods to detect and calculate the concentration difference of the drug in the perfusion fluid at different time points and the blood plasma concentration of the rat during the perfusion,obtain the absorption behavior parameters of oral PPI in rat intestines which are apparent permeability coefficient(P_eff),absorption rate constant?K_a?and steady-state blood drug concentration(C_ss).We speculate that the duodenum may be the best absorption site for all oral PPIs.Ilaprazole and its sodium salt have higher intestinal absorption efficiency and more stable absorption performance more than rabeprazole sodium and esomeprazole magnesium.In addition,after intravenous injection or oral gavage administration of¹⁴C radiolabeled ilaprazole and esomeprazole magnesium in rats,we found that ilaprazole and esomeprazole magnesium's retention time in the target tissue?stomach?is longer.The drug concentration in the stomach changes more smoothly,and the accumulated drug content is higher than other organs within 24 hours.In addition,it was found that the accumulation of ilaprazole in the target tissue showed a specific distribution,because it was mainly located in gastric mucosal cells.Our research provides valuable reference and guidance for the future development or optimization of new oral preparations containing PPIs.