Download I. Concept de clairance (in vivo)

Clearance: basic concept
(in vitro)
Update OCT 2010
Clearance: definition
Clearance =
Clearance =
Rate of elimination
driving concentration
dx /dt
driving
concentration
mass x T-1
= mass x V-1
=
= V x T-1
Amount/Time
concentration
Clearance :
from in vitro to in vivo
In vitro clearance
cell
dx/dt
analyte
Driving concentration = constant
intrinsic
Clearance =
dx/dt
Cst
= Volume of the solution totally
cleared by time unit
= operational definition
Clearance: in vitro vs. in vitro
Taking into account the analyte input
analyte (Cin)
°
Q
(Cout)
Limiting factors
°
•
analyte supply = Q x (Cin)
•
capacity of the system to clear: Clint
Clearance : in vitro vs in vivo
analyte
• In vitro
Diffusion
• In vivo
analyte
°
Flow (Q)
Diffusion
Clearance: general model
o
Q x Cin
o
Q x Cout
o
Q x (Cin - Cout)
Cl =
dX /dt
Cin
o
=Qx
(Driving concentration)
[Cin - Cout]
Cin
o
=QxE
flow
extraction
coefficient
(ratio)
Clearance: general model
Clorgan = Qorgan x Eorgan
organism
Flow
organism
Floworgan
organism
organism
extration ratio (0 to 1)
no unit
Cl is the blood (plasma) volume which is totally cleared of
the drug for a time unit.
Clearance is expressed in terms of flow which makes its
interpretation difficult for a clinician
Relevance of the clearance concept
• Quantifies elimination
• Is usually constant ( a parameter)
• Parameter controlling exposure (AUC)
Relevance of the clearance concept
• For its usefulness
–e.g.: dose computation
• For its mechanistic value
–understanding of mechanism
Application of the clearance concept
1. To the whole body
– plasma clearance (body, blood)
2. To a specific organ
– liver / kidney / others
3. in vitro systems
– hepatocytes
(extrapolation from in vitro to in vivo)
Application of the clearance concept
• Classification of clearances (Cl)
By organ
• liver : Clh
• kidney : Clr
By mechanism
• metabolic clearance (Clh)
• excretion clearance (Clr)
With respect to the matrix fluid
• blood
• plasma