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The following message was posted to: PharmPK
What Is Clearance?
The comments on this listserv seem to indicate that there is
considerable confusion between methods of calculation of clearance
and the fundamental definitions or meaning of clearance. First, let
us assume that we are considering an elimination mechanism rather
than dealing with distribution clearance.
There are many methods of calculation of clearance depending on
the experimental setup and what is being measured. These calculation
methods include: Dose/AUC, Elimination Rate or Excretion Rate divided
by Plasma (or Blood) Concentration, Flow times Extraction Ratio,
Elimination Rate Constant times Volume of Distribution, and fitting
for CL within a model equation. None of these are definitions of
Clearance but might represent or range from an 'apparent clearance'
to the true clearance. All lead to a useful numerical value that can
then be considered further in light of assumptions, quantitative and
predictive needs, and mechanistic context.
The true meaning of CL depends on the processes controlling loss
of drug from the system. For drug metabolism, CL might be Vmax / Km
for the biotransformation process. For renal excretion, CLR might be
GFR or GFR coupled with secretory and reabsorptive transport
parameters. Sometimes there are intervening binding, blood flow, or
permeability / transport mechanisms that alter availability of the
drug to the true or final elimination or excretion step and these
appear in various equations, eg, Systemic Clearance for an Organ
Clearance Model is Q x CLint / (Q + CLint) where CLint is Vmax / Km
for metabolism (i.e. Intrinsic Clearance) for the "well-stirred"
hepatic model. All of this indicates that Clearance is a
quantitative term that represents the biochemical and physiological
capability of the system for removing specific drugs. Sometimes
binding and distribution elements are part of 'apparent clearance'
and can often be dissected from the relationship to get to the true
mechanistic component that causes loss of drug from the system.
These removal mechanisms do not depend on drug concentration per se,
although when capacity-limited, the drug concentration can be
factored in, viz. the Michaelis-Menten equation for metabolism.
Elimination Rate is simply Clearance x Substrate Concentration.
This is sometimes a simple, straight-forward calculation but often
begs the question of what clearance mechanisms are operative and
where is the substrate concentration (blood, plasma, unbound drug,
tissue, intracellular) if one is dissecting the system into its
molecular and mechanistic components. On the other hand, there is
less ambiguity of Elimination Rate is one is making measurements
directly of output from the system.
Perhaps Clearance is somewhat "in the eye of the beholder" as it
may have various levels of functional use but it serves
pharmacokinetics well ranging from teaching introductory concepts to
exploring fundamental mechanisms of drug disposition.
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The following message was posted to: PharmPK
s.o.o
Just simply defination of clearance in all aspects of pharmaceutical
sciences I mean Pharmacokinetics, Biopharmaceutics, clinical
pharmacology, etc. They may be no single defination of clearance.
Summarize it is quite interesting
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)