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The following message was posted to: PharmPK
Often oral CL is calculated in the absence of any info
on F; I believe even WinNonlin using non-compartmental
analysis does it (Dose/AUC). Without having IV data,
is it useful to calculat oral CL?
Rostam
[Please don't use 'oral clearance'. It must be the most misleading of
PK terms. If you must quote the number use Cl/F so the reader doesn't
forget the 'F'. - db]
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Well, for starters the Cl/F predicts steady-state plasma
concentrations. Moreover, if you can answer any of the following
questions with any degree of certainty you might be able to add to a
physiological interpretation of Cl/F:
Is intrinsic clearance expected to be low or high?
Is Cl/F substantially larger than hepatic blood flow?
What are the biopharmaceutical classification characteristics
of the compound?
Does Cl/F change dramatically with formulation, fed/fasted
state, inhibitors/inducers, etc...?
This is a short list. There are many more that could be included.....jw
Jeff Wald, PhD
Clinical Pharmacokinetics/Modeling and Simulation
Neurology and GI
RTP, NC
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The following message was posted to: PharmPK
Jeff,
It was very nice to hear from you again. Your points
are all well taken and we all know they are relevant
if you know the F. My question was: in the absence of
F, is it appropriate to calculate oral clearance which
many people (including David) believe is not an
appropriate term (although well respected PK books are
using it)?
Rostam
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Rostam - Nothing in my first note was predicated on knowing F. One
only ever has an estimate of a particular quantity. The point of my
note was that if you can estimate F or intrinsic clearance, even if
your estimates are imperfect (or possibly even speculative), from some
other source of information you can then interpret Cl/F in a
physiological context. I just listed some different ways of informing
the values of the numerator and denominator of CL/F independent of each
other.
As for semantics, I am ambivalent. I am perfectly happy with oral
clearance as a description, but Cl/F is shorter to type.
Jeff
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The following message was posted to: PharmPK
Dear Jeff,
Thank you for your comments with respect to the meaning of 'oral CL' or
Cl/F. I agree.
> As for semantics, I am ambivalent. I am perfectly happy with oral
> clearance as a description, but Cl/F is shorter to type.
On this point I agree with David Bourne. I don't like the term 'oral
clearance' because it does match to the definition of clearance, a
primary
concept in pharmacokinetics. Could anyone give a clear definition of
'oral
clearance' that give really insight in what it is? Of course, 'oral
clearance' is 'oral dose divided by AUC' but I cannot accept this as a
definition with a physiological or mechanistic meaning. So for me the
term
'oral clearance' is meaningless.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.rug.nl
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The following message was posted to: PharmPK
Hans Proost wrote:
> On this point I agree with David Bourne. I don't like the term 'oral
> clearance' because it does match to the definition of clearance, a
> primary
> concept in pharmacokinetics. Could anyone give a clear definition of
> 'oral
> clearance' that give really insight in what it is?
Clearance is the factor that relates the rate of elimination to the
driving drug concentration. If we consider the average steady state
concentration then the rate of elimination will be proportional to the
input rate. The oral clearance can then be defined as the relationship
between the oral dose rate and the average steady state concentration.
The usual proportionality constant relating oral dose rate to actual
input rate is F -- the extent of bioavailability.
We should also remember that very commonly the measured concentration
is only proportional to the true driving force -- the unbound
concentration.
It seems that most people are happy to talk casually about clearance
based on total drug concentration with an implicit proportionality
constant of the unbound fraction so I feel quite comfortable with the
concept of oral clearance which has another implicit proportionality
constant.
Please note that clearance is not defined by dose/auc. This is just a
convenient calculation trick to estimate clearance. Equally clearance
is not defined as the volume of plasma cleared per unit time. This is
only a statement of the units of clearance without defining what is
actually means to a pharmacokineticist.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dear Hans
For what it's worth, I also consider the term 'oral CL' not only
inappropriate and wrong, but most of all dangerous. Especially with
respect to students or all of those who are starting or wanting to
understand pharmacokinetics. Unarguably perhaps the worst PK problem
ever has been always nomenclature and notation. However, in this case,
by definition, clearance cannot be perceived as anything else than
instantaneous rate of change divided by instantaneous concentration.
Only if one integrates that expression, the Dose by AUC ratio comes
about, but no confusion ought to be made about what Dose one is talking
about. It only makes sense to consider the amount of drug that elicits
the observed concentration versus time profile. So, if an extravascular
administration is under consideration, the only possible dose of
interest is the biovailable dose, meaning the actual amount that
entered the systemic circulation. If one insists in referring to the
administered Dose, then the bioavailability factor F comes into place.
But if algebraically one chooses to attach it to the CL estimate that
should not alter the meaning of such an important PK parameter. It can
only refer to volume cleared per unit time, without any relationship
whatsoever to mass. This concept may be extended to any clearing organ
or system, such as in the definitions of renal CL, hepatic CL,
pulmonary CL, billiary CL, saliva CL, breast milk CL, and so on, but
please don't spread the term 'oral CL' no more.
Thank you.
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.-at-.bos.mcphs.edu
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The following message was posted to: PharmPK
Hi Nick,
You stated: The usual proportionality constant
relating oral dose rate to actual input rate is F --
the extent of bioavailability. If you are referring to
F = (Div x AUCo) / (Do x AUCiv), would you please
clarify which term represents oral dose rate and which
one actual input rate?
Rostam
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The following message was posted to: PharmPK
Rostam
F * oral dose rate = actual input rate
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
I agree with David. Oral clearance is misleading terminology. It implies
that clearance is generally different for oral doses. It can be when gut
metabolism is involved, but that is not how it's being used. Just
because a term is used in print doesn't make it correct.
For example, in years past, the term "absorption" was widely used to
refer to systemic availability (for example, in in vitro - in vivo
correlation using Wagner-Nelson or Loo-Riegelman methods). Absorption is
now defined (by the FDA and others) as entering the apical membrane of
the enterocytes. We all know the intestinal lumen is outside the body. A
drug molecule is absorbed when it enters the body, which requires only
entering the apical membrane - it is now in the cell and can affect the
organism. However, it may not reach even the portal vein, much less the
systemic circulation.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Dear Nick, Luis, and Walt,
Thanks for your contributions.
Nick wrote:
> If we consider the average steady state
> concentration then the rate of elimination will be proportional to the
> input rate. The oral clearance can then be defined as the relationship
> between the oral dose rate and the average steady state concentration.
I'm sorry, but I don't like this approach. First, you need the
consideration
of average steady state, which is rather artificial here. Second, a
definition of clearance in terms of dose rate is quite different than
that
in term of rate of elimination. Plasma drug concentration is not the
driving
force for drug input.
> We should also remember that very commonly the measured concentration
> is only proportional to the true driving force -- the unbound
> concentration.
I agree that the focus on total concentration is not the best approach
in a
mechanistic sense, since unbound concentration is the actual driving
force.
However, total concentration is at least related to this driving force,
and
thus is at least results in a useful concept.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.rug.nl
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The following message was posted to: PharmPK
Hi Hans,
Thanks for your comments. In my opinion the term oral
CL is meaningless if F is unknown. In a physiological
sense CL is CL and remains constant (if there is no
saturation of absorption or elimination): CL Div/AUCiv = (Do/AUCo) x F
Nick, how do you calculate actual input rate without
knowing F. I am trying to understand the practical
application of this equation: F * oral input rate actual input rate.
Rostam
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The following message was posted to: PharmPK
Hans,
Hans Proost wrote:
> Nick wrote:
>
> > If we consider the average steady state
> > concentration then the rate of elimination will be proportional to
the
> > input rate. The oral clearance can then be defined as the
relationship
> > between the oral dose rate and the average steady state
concentration.
>
> I'm sorry, but I don't like this approach. First, you need the
> consideration
> of average steady state, which is rather artificial here. Second, a
> definition of clearance in terms of dose rate is quite different than
> that
> in term of rate of elimination. Plasma drug concentration is not the
> driving
> force for drug input.
I think you are misinterpreting what I wrote. I did not say and would
not say that plasma drug concentration was the driving force for drug
input.
> > We should also remember that very commonly the measured
concentration
> > is only proportional to the true driving force -- the unbound
> > concentration.
>
> I agree that the focus on total concentration is not the best approach
> in a
> mechanistic sense, since unbound concentration is the actual driving
> force.
> However, total concentration is at least related to this driving
force,
> and
> thus is at least results in a useful concept.
>From a pharmacodynamic perspective the total drug concentration is
always contaminated by the plasma protein binding. From a PK
perspective plasma protein binding is of no consequence (except in some
special and hardly ever observed cases for high extraction ratio
drugs). If the chemical analysts did a proper job of measuring unbound
concentration we would know more about PK and PD instead of having to
waste energy on these endless debates about plasma protein binding.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Rostam,
Rostam Namdari wrote:
> Nick, how do you calculate actual input rate without
> knowing F. I am trying to understand the practical
> application of this equation: F * oral input rate actual input rate.
Think of a number between 0 and 1 and you have the answer :-)
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Dear on the list,
Gibaldi&Perrier's book (Pharmacokinetics Marcel-Dekker 2nd ed 1982, well
respected one, I guess) introduces what they call 'apparent oral
clearance' as D_oral/AUC_oral, but at the same time these authors
assume all dose administered was absorbed from an intestine and entered
into a portal vein. Thus their clearance might probably be called
'portal vein-hepatic clearance' or so. I don't have the book at hand
right now, but as I remember in what follows, these authors relate their
Cl_oral to Cl_I (intrinsic clearance) in an imprecise (not to say
flawed) way, though their result may serve as a certain approximation.
If an absorption is inclomplete such a clearance is no longer
D_oral/AUC_oral and it cannot be determined solely on a base of blood
samples taken from main circulation. This case I agree calling
D_oral/AUC_oral as 'oral clearance' is meaningless.
Best regards
Wojciech Jawien
Jagiellonian University
ul. Medyczna 9
30-688 Krakow, Poland
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Dear on the list,
Gibaldi&Perrier's book (Pharmacokinetics Marcel-Dekker 2nd ed 1982, well
respected one, I guess) introduces what they call 'apparent oral
clearance' as D_oral/AUC_oral, but at the same time these authors
assume all dose administered was absorbed from an intestine and entered
into a portal vein. Thus their clearance might probably be called
'portal vein-hepatic clearance' or so. I don't have the book at hand
right now, but as I remember in what follows, these authors relate their
Cl_oral to Cl_I (intrinsic clearance) in an imprecise (not to say
flawed) way, though their result may serve as a certain approximation.
If an absorption is inclomplete such a clearance is no longer
D_oral/AUC_oral and it cannot be determined solely on a base of blood
samples taken from main circulation. This case I agree calling
D_oral/AUC_oral as 'oral clearance' is meaningless.
Best regards
Wojciech Jawien
Jagiellonian University
ul. Medyczna 9
30-688 Krakow, Poland
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