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We have been frustrated with the definition of clearance for a while and
cannot finish our paper. So I am sending this email to you and hope to
get some help.
The definition of clearance:
total body clerance: CLs = rate of elimination / reference
concentration (1) (Gibaldi and Perrier).
This definition should be the instantaneous clearance. It changes with
time. Only for certain cases such as linear, CLs is a constant.
Based on definition (1), it was derived that CLs= integration of rate of
elimination / AUC (2) (Gibaldi and Perrier).
In fact, CLs in Equation (2) has a different meaning from CLs in
(1). CLs in equation (2) is the mean value over time. Only if the
instantaneous clearance (in equation 1) is a constant, then both CLs in
two equations are the same.
organ clearance definition: CL=Q(Cin-QCout)/Cin (3)
If definition (3) is only for steady state situation, then only those
organs that eliminates the compound would have a non-zero clearance. If
applying definition (3) to any organ under non-steady state, then
non-elimination organ would also have clearance. Some people call the
mass transfer between different compartments as clearance. In addition,
applying definition (3) to non steady state, CL could be a non-constant.
Wilson has a very good paper on clearance. that paper cleared a lot of
the confusion. However, it is still confusing the way how clearance is
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Hi Xiaofeng - My point of reference is the basic definition of
clearance dating back well before the advent of PK as a field in its
cl = velocity/substrate concentration
You have pointed out examples of different options for observing the 2
key variables in the relationship, but the intellectual construct
remains the same. So if we calculate cl as dose/AUC I know what we
really have is (Dose/T)/Cp (i.e., AUC = cp*t), or a slight modification
for a zero-order infusion Ko/Cpss where Ko is of course the total
You have also pointed to Fick's law of perfusion where Cl
=Q(Cin-QCout)/Cin in which the velocity of the reaction is equal to
Q*Cdiff and the substrate concentration is defined as Cin.
Depending on the variant, Cl is an instantaneous quantity or
Nonlinearity is another story because the most typical profile that we
deal with (Michaelis-Menten) is derived on the basis of 2nd order
kinetics. Nevertheless, it comes down to a basic structure that is now
familiar...Cl = Vmax/(Conc + km) where the numerator is the maximal
velocity of the reaction and the denominator contains the sum of
concentration + constant (where km is in units of concentration).
All the best, Jeff
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