体外代谢清除率模型用于药物肝代谢过程的研究黄峰.pptxVIP

体外代谢清除率模型用于药物肝代谢过程的研究黄峰第1页/共20页 In vitro methods to predict metabolic clearance rate of Drugs hepatic metabolism第2页/共20页 ContentsPreclinical prediction theoryMathematical ModeAccuracy studyThe problem to be solved第3页/共20页 90% of medicines are mainly involved in the biological conversion of ——P450.The liver is the main organ of drug metabolism .In vitro model has been successfully used to predict in vivo studies of liver metabolism .Preclinical prediction theory第4页/共20页 Theoretical basisPremise:base in the hepatic metabolismThe first step:Parameters obtained in vitro—intrinsic clearanc=ClintThe seceond step:using SF change the Clint and then using the model and this result to Predict in vivo clearance.Iwatsubo T, Hirota N, Ooie T,et al.Pction of in vivo drug metabolism in the human l iver from inredi vitro metabolism data.[J].Pharmacol Ther, 1997, 73(2): 147.第5页/共20页 About CLint Michaelis-menten equationC drug《 KmRemember：Clear all the metabolites (1—1)CLint = Vmax / KmCLint = V0 / S第6页/共20页 When Metabolites is not clear第7页/共20页 General Process——Another methodDrug half-life =T1/2(1—2) CLint =0.693V/ T1/2 第8页/共20页 Relevant conversion factors — Scaling factors(SF)SF is a conversion factor. SF is used to translant Clint to the liver clearanc eg: In the liver microsomes experiment, SF ‘s value is often used containing 45 mg microsomal protein per gram of liver (Rats and human).第9页/共20页 Mathematical modelThere are three models using to predict in vivo clearance:Well-stirred modelParallel tube modelDispersion modelThese models can use the Clint to calculate the liver clearance第10页/共20页 Mathematical modelWell-stirred model Or venous equilibrium modelFree drug concentration in blood vessels is equal to the drug concentration in liver cells.第11页/共20页 Mathematical modelParallel tube model Concentration decreased第12页/共20页 Mathematical modelDispersion modelMore complicated formula, b