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Hi
I would like to know the meaning of "oral clearance". Is it
meaningful only in nonlinear PK situations?
We know that Rate = CL * Reference Concentration (usually plasma
concentration). If we integrate this expression, we will get CL =
total amount eliminated/ AUC or CL = Dose / AUC. Here by dose, I mean
the amount which has entered the circulation. If a drug has linear
pharmacokinetics and the physiological factors remain unchanged and
different doses are given intravenously then CL determined from the
above equation will remain unchanged. As AUCs will be proportional to
the dose. So now in the same previous situation, if we imagine an
oral dose also with a bioavailability of 0.75, then the actual amount
in the blood will be 75% of the dose administered. If this
bioavailable amount is with in the linear PK range of the drug, then
the CL (which now is oral clearance) will be same as that after
intravenous dose. As, in this situation also the AUC will be
proportional to the bioavailable dose.
So, oral clearance will be same as true clearance (after iv dose) in
linear PK range?
Thanks
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dear all
Oral dose CL we can't calculate because the total amount of drug
administered is not reaching the systemic circulation 100%. hence
oral dose CL is not possible to calculate.
i hope this clear for you.
thanks
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The following message was posted to: PharmPK
Dear Millin Karthik,
Actually, it is possible to determine PK parameters including CL from
oral
data - sometimes. We and our users have done this many times over the
years
using GastroPlus when there are sufficient data at more than one dose
level.
Fitting a model to all doses simultaneously, we often find that there
is a
single set of model parameters that best fit all the data. Fitting
individual dose data does not, in general, allow this (unless the
bioavailability happens to be virtually 100%).
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-a-.simulations-plus.com
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The following message was posted to: PharmPK
Sunil
You may find in the PharmPK archives several good discussions about
this (March05, Jan.06). Very unfortunately the term 'oral clearance'
is a terrible misnomer that continues to contaminate the literature
and pursue us all. I can only make mine the words of so many others:
don't say it, it's meaningless, wrong and dangerous. In a nut shell,
I may try to explain that the concept of clearance doesn't have
anything to do with absorption, being essentially independent of the
dose for linear systems. Even with nonlinear systems, it becomes
dependent on the drug concentration presented to the clearing organ,
but never on the bioavailability, by definition. A quick dimensional
analysis shows clearly that CL units have no mass term. But since
bioavailability (BA) is adimensional, thus its silent misleading
role. Perhaps the relationship responsible for the confusion is the
ratio between Dose and AUC, as you mention, which for an iv
administration is self-explanatory. However, for extravascular
administrations, the only interpretation of Dose responsible for a
given AUC is not the administered dose, but rather the bioavailable
dose (drug that didn't enter the body will produce no area!). It's
really a pre-requisite for CL to be an identifiable parameter the
fact that BA is known. However, for practical reasons, as we so often
do in PK (e.g. think about V/F), whenever we have only one equation
with two unknowns, we lump them together and proceed to solve the
equation. But this purely algebraic strategy doesn't confer any
meaning to CL/F other than the ratio of two unknowns that should
always be explicitly mentioned. Clinically this might just be enough
for decision making if formulation, via of administration and
ultimately BA are fixed. However, this should never be coined as a
new parameter independent of those factors. The artifacts may be
extremely significant.
Luis
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)