体外代谢清除率模型用于药物肝代谢过程的研究黄峰
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Drug half-life =T1/2
CLint =0.693V/ T1/2 (1—2)
Relevant conversion factors
— Scaling factors(SF) ➢SF is a conversion factor. ➢SF is used to translant Clint to the liver
Mathematical model
✓Well-stirred model Or venous equilibrium model
Free drug concentration in blood vessels is equal to the drug concentration in liver cells.
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.
THANK YOU
谢
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).
Mathematical model
Theoretical basis
• Premise:base in the hepatic metabolism
• The first step:Parameters obtained in vitro—intrinsic clearanc=Clint
• The seceond step:using SF change the Clint and then using the model and this result to Predict in vivo clearance.
About CLint
Michaelis-menten equation
CLint = V0 / S C drug《 Km
CLint = Vmax / Km
(1—1)
Remember：Clear all the metabolites
When Metabolites is not clear
General Process ——Another method
Mathematical model
✓Parallel tube model
Concentration decreased
Mathematical model
✓Dispersion model
More complicated formula, but closer to physiological conditions
In vitro methods to predict metabolic clearance rate of Drugs hepatic metabolism
Major: chinese traditional medicine Name: 黄峰
（ 2110948107）
Contents
Preclinical prediction theory Mathematical Mode Accuracy study The problem to be solved
There are three models using to predict in vivo clearance:
Well-stirred model Parallel tube model Dispersion model
These models can use the Clint to calculate the liver clearance
• Correct use of SF • Accurate measurement of the
concentration of target compounds • Precise choice in the model of liver
metabolism
the end Thank you
谢
The impact of different species
CLint vivwenku.baidu.com/CLint vitro=SFanimal
(1—4)
Problems
There are some problems in the vitro method
Problems
Error out of range(2 multiple)
Preclinical prediction theory
The liver is the main organ of drug metabolism .
90% of medicines are mainly involved in the biological conversion of ——P450. In vitro model has been successfully used to predict in vivo studies of liver metabolism .
(1—3)
Shibata et al. Designed a new way to ignore the drug and protein and tissue binding
Accuracy study——Ⅱ
Ⅱ. The choice of Scaling factors(SF)
If you use Rats to do vitro research,you have to use some sf to change to human’s clearance
How to choose
➢These three models fit for Drugs with low clearance.
➢the drug ‘s way to metabolize
Comparison of three models Dispersion model can give a better fitting results
The predicting result is far from the true result. People Set the standard is in the 2 multiple.
Enzyme Kinetic model of choice
Advanced issues
• The current study focused mostly in different vitro systems such as selection and Optimization.
Accuracy study——Ⅰ
I. The impact of protein binding
Obach et al. Comparison of 14 kinds of compounds in
vivo, in vitro clearance
Average-folderror=10(log(practictal/actual))/n
CLint =0.693V/ T1/2 (1—2)
Relevant conversion factors
— Scaling factors(SF) ➢SF is a conversion factor. ➢SF is used to translant Clint to the liver
Mathematical model
✓Well-stirred model Or venous equilibrium model
Free drug concentration in blood vessels is equal to the drug concentration in liver cells.
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.
THANK YOU
谢
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).
Mathematical model
Theoretical basis
• Premise:base in the hepatic metabolism
• The first step:Parameters obtained in vitro—intrinsic clearanc=Clint
• The seceond step:using SF change the Clint and then using the model and this result to Predict in vivo clearance.
About CLint
Michaelis-menten equation
CLint = V0 / S C drug《 Km
CLint = Vmax / Km
(1—1)
Remember：Clear all the metabolites
When Metabolites is not clear
General Process ——Another method
Mathematical model
✓Parallel tube model
Concentration decreased
Mathematical model
✓Dispersion model
More complicated formula, but closer to physiological conditions
In vitro methods to predict metabolic clearance rate of Drugs hepatic metabolism
Major: chinese traditional medicine Name: 黄峰
（ 2110948107）
Contents
Preclinical prediction theory Mathematical Mode Accuracy study The problem to be solved
There are three models using to predict in vivo clearance:
Well-stirred model Parallel tube model Dispersion model
These models can use the Clint to calculate the liver clearance
• Correct use of SF • Accurate measurement of the
concentration of target compounds • Precise choice in the model of liver
metabolism
the end Thank you
谢
The impact of different species
CLint vivwenku.baidu.com/CLint vitro=SFanimal
(1—4)
Problems
There are some problems in the vitro method
Problems
Error out of range(2 multiple)
Preclinical prediction theory
The liver is the main organ of drug metabolism .
90% of medicines are mainly involved in the biological conversion of ——P450. In vitro model has been successfully used to predict in vivo studies of liver metabolism .
(1—3)
Shibata et al. Designed a new way to ignore the drug and protein and tissue binding
Accuracy study——Ⅱ
Ⅱ. The choice of Scaling factors(SF)
If you use Rats to do vitro research,you have to use some sf to change to human’s clearance
How to choose
➢These three models fit for Drugs with low clearance.
➢the drug ‘s way to metabolize
Comparison of three models Dispersion model can give a better fitting results
The predicting result is far from the true result. People Set the standard is in the 2 multiple.
Enzyme Kinetic model of choice
Advanced issues
• The current study focused mostly in different vitro systems such as selection and Optimization.
Accuracy study——Ⅰ
I. The impact of protein binding
Obach et al. Comparison of 14 kinds of compounds in
vivo, in vitro clearance
Average-folderror=10(log(practictal/actual))/n