- On 16 Jan 2003 at 09:45:20, Xiaofeng Wang (xiaofeng.wang.-a-.bms.com) sent the message

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The following message was posted to: PharmPK

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 - On 16 Jan 2003 at 10:36:03, Jeff Wald (JWald.-a-.Pharsight.com) sent the message

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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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