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Dear everyone:
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
equation
(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
used.
xiaofeng wang
Bristol-Myers Squbbi
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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
own right:
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
Dose/T.
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
time-averaged value.
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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