| Gene PIM-1 is a member of the gene pim family（PIM-1,PIM-2,PIM-3）,PIM-1 kinase plays a very important role in the regulation of apoptosis,differentiation,proliferation and tumorigenesis.PIM-1 protein as a new drug target possesses high selectivity,which receives increasing attention in recent years.Compound KY-C002（Fig.1）is an excellent PIM-1 kinase inhibitor,which can be used for preventing and treating cancer,autoimmune diseases,allergic reactions and other diseases.Therefore,compound KY-C002 has a positive clinical significance.Meanwhile,there are no researches reported on the characteristic of its biopharmaceutics.In this study,the bioavailability of small molecule PIM-1 kinase inhibitor（KY-C002）was studied using the Caco-2 cell monolayer model and rat intestinal absorption model.This study helped providing bio-pharmacological basis for the oral absorption parameters of KY-C002and the development of novel dosage form with high oral bioavailability.Firstly,we studied the physicochemical properties of the KY-C002 and established the HPLC method.Then,we confirmed that the established Caco-2 cell monolayer model is suitable for evaluating transcytosis capacity of chemical drug by observing the cellular morphology,determining the transendothelial electric resistance（TEER）and testing phenol red permeability under laboratory conditions.Finally,the characteristics of biological pharmaceutics of KY-C002 was studied using rat model of intestinal absorption.The results demonstrated that the established HPLC detection method for KY-C002 is simple,sensitive,liable and good specificity,which meets the requirements of quantitative analysis.The growth and differentiation of constructed Caco-2 cell monolayer are well enough to serve as in vitro intestinal absorption model.The results of Caco-2 cell monolayer transcytosis and rat intestinal absorption indicated the concentration has a significant influence on the transcytosis of KY-C002.In detail,the apparent absorption coefficient(Papp)of KY-C002 can reach a maximum value at a concentration of 10μg/m L.The absorption site of KY-C002 is primarily located in duodenum and jejunum.The KY-C002 is the substrate of P-gp and thus cannot be influenced by the efflux effect of P-gp.The KY-C002 can be absorbed well and enter into the systemic circulation to perform its biological activity. |
