Pharmacokinetics And Tissue Distribution Of CFTR Inhibitor In Mice

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane chloride ion channel protein. It belongs to a family of protein which is an ATP-binding protein-ABC as a superfamily. CFTR chloride channel plays an important role in many physical activities. Its mutation will cause the CFTR chloride channel can not be running a normal ion transport function, cystic fibrosis (CF) is caused by CFTR mutation, which involving many epithelial tissues and organs.Presently, The treatment of CF has not yet found an ideal animal model. Gene targeting technology targeted gene knockout (no protein product expression) or site-directed mutagenesis (mutation expression of pathogenic protein) only in mice in vivo, gene targeting carried out in large animals there is no attempt to report the success. The existing mouse CF model as with human respiratory submucosal glands located in various, CF lung phenotype in the mouse model is not fully down, so it needs a better simulation of human CF pathology large animal model. Another possible strategy is the useing of inhibitors induce CFTR "functional knock out". It will use a specific, high-affinity CFTR inhibitors in large animals continued to inhibit CFTR chloride channel function. CFTR inhibitors will be in the establishment of CF large animal models play an important role.The research group used high-throughput screening (HTS) small-molecule compounds selected a high-affinity, new, and pig-specific small-molecule CFTR inhibitor pCFTR_inh-A. Existing experiments have proved, pCFTR_inh-A in vitro to inhibit all known activators of the CFTR chloride channel activation. As the physiological and pathological models in mice compared with pigs and other large animals, it is easier to build, and the mice is drawn easily, so we firstly study the pharmacokinetics and tissue distribution of pCFTR_inh-A in mice. It will provide the basis to study the establishment of large animal pig model of cystic fibrosis and the root causes of CF disease and find effective treatment approach of great significance.pCFTR_inh-A is a pig CFTR specific inhibitor. In this experiment 20 mg·kg?1 pCFTR_inh-A was given by intraperitoneal injection to study the pharmacokinetics and tissue distribution of pCFTR_inh-A in mice. HPLC method for the determination of pCFTR_inh-A in plasma and tissues was established and applied to determine pCFTR_inh-A in plasma and tissue samples. The plasma concentration-time curve of pCFTR_inh-A conformed to drug was found after 5 minutes. The pharmacokinetic trait of pCFTR_inh-A exhibited that it was quick while elimination was slow and high bioavailability. The distribution of pCFTR_inh-A exhibited specific characteristics and it was the highest in liver, kidney and lung, while lower in heart, spleen and intestines, and lowest in brain. To observe the pharmacokinetics and tissue-distribution characters of pCFTR_inh-A will be use of creating Cystic fibrosis phenotype in large animals.