Optimization And Verification Of In Situ Vascularly Perfused Rat Intestine-liver Preparation In Drug Absorption

Objective:To optimize the in situ vascularly perfused rat intestine-liver preparation andverify its feasibility in predicting drug absorption．Method：The perfusion conditions were optimized，respectively，the Krebs-Ringer solutionwith bovine serum albumin and mannitol and the Krebs-Ringer solution with bovine serumalbumin and dextran-T40were contrasted for finding out the best perfusate medium；TheLC-MS/MS assay of three kinds of alkaloid(oxymatrine、matrine and sophocarpine)and sixkinds of organic acid(chlorogenic acid、caffeic acid、ferulic acid、cinnamic acid、glycyrrhizic acid and glycyrrhetic acid)were developed in perfusate、rat plasma andHBSS，respectively；The perfusing absorptivity of these9compounds were evaluated bythe optimal in situ vascularly perfused rat intestine-liver preparation；The pharmacokineticproperties and Fabsof9compounds were studied in vivo in rats；The Caco-2cell monolayermodel was established to study the bidirectional transport of9compounds．The correlationamong perfusing absorptivity、PappA→Band Fabswere analyzed by the grey correlationanalysis method．Result:It was more economically and exactly to predict the drug absorption with theoptimal in situ vascularly perfused rat intestine-liver preparation； The perfusingabsorptivity values of oxymatrine、matrine、sophocarpine、chlorogenic acid、caffeic acid、ferulic acid、cinnamic acid、glycyrrhizic acid and glycyrrhetic acid were8.30%、14.03%、 12.03%、1.37%、2.68%、59.00%、85.59%、0.47%and88.73%，respectively；Their Fabsvalues were15.69%、53.4%、39.63%、3.59%、14.7%、64.91%、81.15%、3.04%and96.72%，respectively；The PappA→Bvalues of these9compounds were（6.39±0.74）×10-6cm/s、（10.7±0.17）×10-6cm/s、（7.35±0.76）×10-6cm/s、（0.66±0.04）×10-6cm/s、（5.05±0.66）×10-6cm/s、（10.24±1.58）×10-6cm/s、（24.30±3.82）×10-6cm/s、（0.28±0.06）×10-6cm/s and（30.57±4.69）×10-6cm/s，respectively；The correlation between perfusingabsorptivity and Fabsand the correlation between PappA→Band Fabswere0.7149and0.7516，respectively， which weren’t found any significant difference according to the greycorrelation analysis（P＞0.05）．Conclusion:The in situ vascularly perfused rat intestine-liver preparation will be foundgood application prospect in the field of drug absorption．...