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I have another basic question. I have noticed that many PK people use
the terms clearance and elimination interchangeably. What is the
correct terminology? Is there instances where the use of clearance is
more appropriate than elimination?
Geo Thompson
gnadakal5.at.yahoo.com
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Clearance is the factor relating concentration to rate of elimination
Elimination Rate = Concentration * Clearance
mg/h mg/L L/h
Elimination has units of mass/time. Clearance has units of volume/time.
They are not interchangeable. It is always inappropriate to use
clearance when you mean elimination rate and vice versa.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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s.o.o
Just to spice up what professor Nick is saying clearance is also an
abstact concept (a theoretical assumption without anatomical or
physiological significance) whereas elimination is not. For instance
it is not easy to clear a particular drug from the blood or urine
completely
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The following message was posted to: PharmPK
If you can say: "For instance it is not easy to clear a particular
drug from
the blood or urine completely", isn't that (effectively) the same as
saying
it is not easy for it to be completely eliminated from the blood or
urine?
Walt
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
>On 1/16/06, Walt Woltoszwrote:
> If you can say: "For instance it is not easy to clear a particular
> drug from the blood or urine completely", isn't that (effectively)
> the same as saying it is not easy for it to be completely eliminated
> from the blood or urine?
Now I'm confused. I had thought that clearance referred to expulsion
from a compartment, while elimination referred to from the entire
body? So you'd clear from blood/urine/tissue compartment, but more
importantly, you'd also eliminate via urine, feces, breath, etc?
best,
-tony
blindglobe.-at-.gmail.com
Muttenz, Switzerland.
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Example: Enzyme X is the only responsible for the elimination of drug
Y via biotransformation. Its conversion rate corresponds to the
intrinsic metabolic elimination rate of the drug. If 1L/min of
'blood' is completely cleared of the drug, that's its metabolic
clearance. This is true whether the efficiency of the process, i.e.
the extraction ratio, is 90% or 10%, which means the conversion may
be almost complete in a single step, or it takes more than one
passage, depending on the enzyme conversion rate.
Clearance = Elimination rate / Concentration
Both the right hand side quantities determine, i.e. are the cause of,
the clearance.
Refs:
"the clearance of a high extraction ratio drug is dependent on blood
flow, but independent of binding in blood or intrinsic metabolic
activity ... a drug with a low extraction ratio shows the opposite
dependence", TN Tozer, Chapter 2. Concepts of Basic Pharmacokinetics
in "Pharmacokinetics: Theory and Methodology", M Rowland & G Tucker
(Eds.)
"clearance may be considered to be that portion of the volume of
distribution of the compound required to supply the quantity of
compound excreted per unit time, rather than the volume of plasma",
JG Wagner, Some Important Pharmacokinetic Concepts in
"Biopharmaceutics and Relevant Pharmacokinetics"
--
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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This is algebra not pharmacokinetics:
> Clearance = Elimination rate / Concentration
>
This is absurd:
> Both the right hand side quantities determine, i.e. are the cause of,
> the clearance.
Neither of your references supports your assertion that elimination
rate or concentration CAUSES clearance.
Clearance is the proportionality factor relating concentration (the
cause) to elimination (the effect). How can you possibly explain how
drug that is being eliminated is the cause of the concentration that
is driving an enzyme to metabolize and thus eliminate the drug?
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.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 Nick
Thanks for the discussion.
Algebra is a branch of mathematics in which symbols represent numbers
or members of a specified set, used to express general relationships
that hold for all members of the set. Pharmacokinetics concerns to
the fate of a chemical entity in a biological system over time.
You're absolutely right that the algebraic relationship
Clearance = Elimination rate / Concentration
just expresses the relationship between the variables, as do the
other two that may also be written with 3 variables. Only the
convention about what is the independent variable suggests the most
useful.
So really the discussion about what causes what is akin to the story
of the chicken and the egg, and therefore frivolous. But conceptually
we can describe the elimination of a drug in many different ways
other than by its clearance. On the other hand, clearance has no
meaning without a background concept of extraction and concentration
'in-and-out'. And thus the form of the above algebraic expression.
I would say that the "drug that is being eliminated is the cause of
the concentration that is driving an enzyme to metabolize and thus
eliminate the drug" just because as drug decays so does the
concentration. For a linear system the ratio is constant and
therefore the clearance. As you know, integrating the right hand side
with respect to time one gets
Clearance = Dose / AUCo-oo
and again the clearance looks much better as the ratio between the
stimulus (the input, the cause, the independent variable) and the
system's exposure to it with time.
I understand your rationale, I just have a hard time agreeing with
it. And since 95% of the textbooks by which I continue to study
provide a different rationale than yours, I just think it makes more
sense.
Best regards.
--
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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Luis,
Thanks for your response. I'm quite comfortable with the fact that
95% of textbooks are wrong and I am right :-)
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.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 Luis, Walt and Nick,
Thanks a lot for your remarkable contributions to this forum. I have
been following the thread of this interesting discussion concerning
the clearance concept and I feel that this kind of debate is what
help us to improve our knowledge of PK basics. In my particular
opinion, I do agree with professor Nick's viewpoint. Concerning Dr.
Luis's inputs, I don't see any reason to say that concentration is
the cause of the clearance.
> Clearance = Elimination rate / Concentration
> Both the right hand side quantities determine, i.e. are the cause
of, the clearance.
I have to disagree with you on this subject. Let me put it into
perspective, you are saying that (even though linearity is a fact) if
drug concentration (cause?) is changing then clearance will be
changing accordingly. I firmly believe that, under linearity
condition, this perception doesn't make much sense. In fact, this is
the basis of superposition principle we conventionally use in
clinical PK for multiple dose regimen calculations, which is
supported by more than 95% textbooks.
Comments are welcomed
Best regards,
Jorge Duconge
[I think this is a new message. Putting PharmPK at the start of the
subject routes incoming messages into my archive folder.
May I quote, (out of context) "even though linearity is a fact".
Linearity is an approximation. With all (most, many) metabolic
proceses (if there isn't cell death etc. first) as concentration
increases clearance changes, as the metabolic processes becomes
saturated. In renal excretion it is (free, unbound) concentration
that drives the filtration process. Transport across membranes is
concentration (aka thermodynamic activity) driven. - db]
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The following message was posted to: PharmPK
Dear Jorge
As I mentioned before, causality is perhaps in the eye of the
beholder. But about the fundamentals I may have not make myself clear.
> you are saying that (even though linearity is a fact) if drug
concentration (cause?) is changing then clearance will be changing
accordingly.
Although linearity, in the sense of dose proportionality, is
certainly not a fact, but rather a result of the amount of drug with
respect to the 'handling' capacity of the body, I never said
clearance changes. In fact I stated it is assumed as constant in
linear systems, the only ones where the superposition principle applies.
Mentioning clinical PK and multiple dosing, I'm sure you know that
with phenytoin, for instance, clearance becomes a function of
concentration for most of the concentration range. And again, not the
other way around.
However, for most drugs, following a linear kinetics, the intrinsic
clearing rate and the concentration presented to the clearing organ
determine the clearance.
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA=A0 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.aaa.bos.mcphs.edu
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The following message was posted to: PharmPK
Dear Jorge
As I mentioned before, causality is perhaps in the eye of the
beholder. But about the fundamentals I may have not make myself clear.
> you are saying that (even though linearity is a fact) if drug
concentration (cause?) is changing then clearance will be changing
accordingly.
Although linearity, in the sense of dose proportionality, is
certainly not a fact, but rather a result of the amount of drug with
respect to the 'handling' capacity of the body, I never said
clearance changes. In fact I stated it is assumed as constant in
linear systems, the only ones where the superposition principle applies.
Mentioning clinical PK and multiple dosing, I'm sure you know that
with phenytoin, for instance, clearance becomes a function of
concentration for most of the concentration range. And again, not the
other way around.
However, for most drugs, following a linear kinetics, the intrinsic
clearing rate and the concentration presented to the clearing organ
determine the clearance.
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA=A0 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.-a-.bos.mcphs.edu
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The following message was posted to: PharmPK
Dear Jorge
As I mentioned before, causality is perhaps in the eye of the
beholder. But about the fundamentals I may have not make myself clear.
> you are saying that (even though linearity is a fact) if drug
concentration (cause?) is changing then clearance will be changing
accordingly.
Although linearity, in the sense of dose proportionality, is
certainly not a fact, but rather a result of the amount of drug with
respect to the 'handling' capacity of the body, I never said
clearance changes. In fact I stated it is assumed as constant in
linear systems, the only ones where the superposition principle applies.
Mentioning clinical PK and multiple dosing, I'm sure you know that
with phenytoin, for instance, clearance becomes a function of
concentration for most of the concentration range. And again, not the
other way around.
However, for most drugs, following a linear kinetics, the intrinsic
clearing rate and the concentration presented to the clearing organ
determine the clearance.
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA=A0 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.aaa.bos.mcphs.edu
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The following message was posted to: PharmPK
Dear All:
I have enjoyed reading this discussion. Please consider this
perspective on
clearance...
Organ clearance may be defined as the product of blood flow and the
extraction ratio, CL(o) = Q(o) * ER, and total body clearance may be
defined
as the sum of all organ clearances.
In the most simple case, all clearance is from a single organ, and total
body clearance may be defined as CL = Q * ER, where Q and ER refer to
the
blood flow and extraction ratio associated with the eliminating organ.
Under steady-state conditions, the extraction ratio may be defined as
(Cin -
Cout)/Cin, where Cin refers to drug concentrations in blood entering the
organ and Cout refers to blood concentrations in blood exiting the
eliminating organ.
For most drugs, the concentration difference (Cin - Cout) will be
determined
by diffusion of drug between blood and sites within the elimination
organ.
Based on Fick's First Law, the determinants of (Cin - Cout) will
include the
concentration gradient between the drug concentration in blood, Cb
(which
will range from Cin to Cout as blood perfuses through the organ), and
the
drug concentration in tissue sites (Ci): i.e., (Cb-Ci). Additional
determinants include: the properties of the diffusion barrier (e.g.,
effective surface area of the "diffusion barrier" [SA], effective
thickness
of the diffusion barrier [h]), and properties of the interaction of
the drug
in the diffusion barrier (e.g., the effective diffusion constant [D]).
Within an elimination organ, Ci will be determined, in part, by "drug
elimination" (e.g., chemical biotransformation, carrier mediated
transport
or diffusion into the bile or urine, etc.).
So, with this view of clearance, does clearance determine
elimination, or
does elimination determine clearance???
At a cellular/molecular level, drug elimination (e.g., the
biotransformation
or expulsion of a drug molecule) leads to a change (reduction) in Ci,
which
drives diffusion of drug from blood to cellular sites (Cb-Ci), which
effectively determines the extraction ratio (Cin-Cout)/Cin and, thus,
determines clearance...
Best regards,
Joe
**
Joseph P. Balthasar, Ph.D.
Associate Professor & Director of Graduate Studies
Department of Pharmaceutical Sciences
University at Buffalo
457B Cooke Hall
Buffalo, New York 14260-1200
Telephone: 716-645-2842 x270
Fax: 716-645-3693
Email: jb.-a-.acsu.buffalo.edu
Web: http://www.acsu.buffalo.edu/~jb/
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The following message was posted to: PharmPK
Dear Jorge,
Thank you for your thoughtful reply.
I think the cause and effect relationships among clearance, volume, and
elimination are such that it is impossible to say that any one is the
"cause" of the other(s).
What causes volume of distribution to be what it is? The underlying
mechanisms of drug partitioning into tissues and interstitial fluids.
What
causes those? Sometimes transporters, which can be saturated, and so
concentration becomes a factor. But it is the affinity of the drug
for the
transporters, and the expression level of the transporters in a
tissue, that
are underlying causes for the volume being what it is. Because of the
affinity and the number of transporters, a volume will be achieved at a
certain concentration, and a concentration will result by the integrated
effects over time.
What causes clearance to be what it is at any given concentration?
Clearly,
the underlying mechanisms are the cause - metabolism, renal filtration,
exhaled parent from lungs, biliary secretion of parent, and so on. I
have
heard no justification for saying that clearance causes any of these.
It is
just one measure of their integrated effects.
As I see it, clearance or elimination are simply two ways of
expressing how
quickly the drug gets out of the system, as observed by changes in
blood or
plasma concentration. In one case we say the amount of drug
eliminated in a
unit time is the amount that would be in a certain volume at the current
concentration. In the other we say so many mass units are eliminated per
unit of time.
Walt
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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Dear Luis,
Thank you very much for your reply. I know that linearity assumption
is only a practical simplification of the real world based on, as you
correctly posted, "the actual relationship between the drug amount to
the handling capacity of the body". In fact, I was just trying to
bring a typical situation (low dosing) into debate, assuming that the
relationship you were mentioning, that is:
Clearance = Elimination rate / Concentration
is merely a rearrangement of the first-order expression (i.e.,
linear) for elimination processes. In this context, I assumed
linearity as a fact (condition). But, get back to the point. Once
again, we must keep in mind that even though the above expression
permit us to CALCULATE clearance from elimination rates and
concentrations values, it doesn't mean clearance depends on both
terms. Speaking of that, one of the most famous legacy from Einstein'
s genius was expressed as the very elegant and well-known equation
E=mc2. It supports the experimental evidence that after impacting a
nucleus with a neutron the released energy (as a photon quantum) is
numerically equal to mass x c2. Recently, some scientists
demonstrated such a relation using accurate data after measuring the
released energy and mass of neutrons (i.e., quantifiable variables).
Logically, the algebraic rearrangement c2=E/m was used. My question
is, would anyone of us simply assert that c2 (i.e., the squared light
speed constant) depend either on energy and/or mass?. I would like to
be on the idea that you agree with me considering clearance, like c2,
as an artifact or a proportionality factor to relate drug
concentration to elimination rate.
On the other hand, if we accept such a statement then we should also
consider that both systemic exposure (AUC) and bioavailability (F)
determines systemic drug clearance. Mathematically yes, but
pharmacokinetically speaking and within the linearity range, drug
clearance is independent of such factors. Accordingly, we can modify
dose, F and AUC metrics in order to verify how these variables alter
clearance value, but we have to know that there are some
physiological constraints to these variations. So, any
bioavailability change will be pharmacokinetically offset with a
corresponding variation in systemic exposure, in such a way that
clearance remains constant (assuming linearity).
Clearance = F x Dose/ AUC
Best regards,
Jorge Duconge
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Dear Joe,
I fully agree with you (see my previous e-mail). It is interesting to
recognize the influence of the domain of expertise on the way of
interpreting pharmacokinetic concepts. It seems that modelers dealing
with mechanism based and physiologically based pharmacokinetic models
approach all these concepts by a different angle.
Best Regards,
Olivier
Olivier Luttringer, Ph.D.,
Modeling & Simulation
Pharmacology Section
Clinical Development & Medical Affairs
WSJ-27.1.14
Novartis Pharma AG
CH-4002 Basel
Switzerland
Tel: +41 61 324 45 68
Fax: +41 61 324 30 39
E-mail: olivier.luttringer.aaa.novartis.com
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The following message was posted to: PharmPK
Dear Jorge
Please be careful since CL = el.rate/Conc has nothing to do with
first order. It's really a model independent definition of clearance.
I really think that the enormous amount of literature on this issue
is by far a much better reference than all my scribbled words.
Anyway, when you state yourself that an expression permits us to
CALCULATE clearance that makes it the dependent variable by
convention. As in your example, one defines Y as a function of X
according to the chosen convention (normally guided by the nature of
the data, as Joseph explained in detail) with the necessary
proportionality constants as per dimensional analysis. Each 3
variables allow three algebraic expressions of them regardless.
So I don't really follow your point since I (and others) said several
times already (as you claim) that CL is a proportionality constant
between rate and C, or amount and AUC. When you say it's independent
of such factors though, again I advise careful since it's really
independent of their ratio for linear systems (and a function of
amount for nonlinear ones).
For those interested I'll just recommend a keen peak at:
"Ch.11 Elimination" in "Clinical Pharmacokinetics - Concepts and
Applications", M.Rowland and TN.Tozer (Eds.)
"Pharmacokinetics, A modern view" (multiple pages), LZ.Benet, G.Levy,
BL.Ferraiolo (Eds.)
"Pharmacokinetics, Mathematical and Statistical Approaches to
Metabolism and Distribution of Chemicals and Drugs" (multiple pages),
A.Pecile and A.Rescigno (Eds.)
"Ch.11 Physiological Pharmacokinetics" in "Pharmacokinetics for the
Pharmaceutical Scientist", JG.Wagner
"Ch.2 Compartmental and Noncompartmental Pharmacokinetics" in
"Biopharmaceutics and Clinical Pharmacokinetics", M.Gibaldi
Et cetera.
Luis
--
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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Dear Luis,
OK. Let me try to put this discussion to rest. If I understood you
correctly, this disagreement is just a matter of viewpoints. I would
rather like to stay myself thinking that your clearance definition is
a very-useful, simple and straight-forward method of calculation for
clearance. Obviously, as Dr. William Jusko argued:
"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."
If you are happy defining clearance as elimination rate to
concentration ratio, go ahead and good luck. I strongly believe we
should go forward. Of course, and again putting Dr. Jusko's words in
my mouth:
"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"
[exception confirms the rule?]
Finally, you typed:
>Please be careful since CL = el.rate/Conc has nothing to do with
>first order. It's really a model independent definition of clearance.
It is not a model independent DEFINITION of clearance. As far as I
aware, there isn't such a thing. Clearance is indeed a model
independent PARAMETER, but the above expression (i.e., a method of
calculation of clearance) definitely came from a model whatsoever.
and regarding first-order kinetic,
mathematicaly:
elimination rate = first-order rate constant X amount
[elimination first-order kinetic]
so, if we use a volume term in order to multiply both side of the
equation, and rearrangement
concentration = amount/volume
clearance=first-order rate constant X volume
then we can express the former equation in term of clearance instead,
which is more physiologically relevant
elimination rate = clearance X concentration
Finally, I want to emphasize that I respect all your remarks and
thoughtful comments, despite my different perspective of this matter.
Best wishes and thanks for such a rewardable debate,
Jorge Duconge
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The following message was posted to: PharmPK
Dear Jorge
I also think that if we maintain the decorum, no difference of
opinions should be an excuse for rudeness. The unsurpassable beauty
of science is that people just need to pick their weapons from the
arsenal of logic and reasoning, and go on respecting each other. So
please don't think that I just want to have the last word, but you
brought up the 'first-order issue' which I find really misplaced.
If you read further into Prof. Jusko's posting "Perhaps Clearance is
somewhat "in the eye of the beholder"" and I might add that if one
continues to philosophically follow the quest for a definition that
doesn't involve a calculation in some algebraic form, then this tread
will continue until we all retire. Anyway please notice that from all
the options for estimating clearance that you cite from Prof. Jusko's
posting, the ratio between instantaneous velocity and instantaneous
concentration, not measurable of course (the conceptual differential
equation, rather than the corresponding difference one), is perhaps
the most abstract concept that maybe relates to the term "true
clearance" used by him. Along these lines I personally find coherence
in the words of Wagner, Gibaldi, Rowland, Tozer and so many others
that I cannot site completely. Definitions may look as pretentious
aspirations when we deal with real data and therefore constant
approximations and compromises. However, academically and
educationally it is important to provide sound goalposts and clear
concepts for those still learning the basics.
A different issue is how you estimate clearance. And for the sake of
correctness, CL certainly may or may not be a model independent
parameter (meaning PK compartmental model) depending on the
assumptions chosen.
For a first order process (only) dM/dt=k.M and CL=k.M/C becomes
CL=k.V , never forgetting the initial assumption.
For a zero order process dM/dt=ko and CL=ko/C (notice same units, vol/
time)
For a second order process dM/dt=k2.M^2 and CL=k2.M.V (again notice
constant units)
For a mixed order process of the type dM/dt=Vmax*C/(KM+C) then CL=
Vmax/(KM+C)
So CL=rate/C has nothing to do with first order. Just too many
references to list.
Using the integrated form, CL=D/AUC, estimating AUC numerically
(trapezoidal, log-trapez., Simpson's rule,...) corresponds to what is
usually denoted by a model independent estimate. If instead one
integrates a single exponential, or a sum of biexponentials
corresponding to some compartmental model, that's normally referred
to as a model dependent estimate.
Thank you and all the participants in this thread for the brain
storming.
Regards to all
Luis
--
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
s.o.o
The issue is does elimination determine clearance or clearance
determine elimination?
With reference to pharmacokinetics total body clearance is Kel.V
where kel is the elimination rate constant and V is the apparent
volume of distribution of drug.From here it is crystal clear that
elimination determines clearance. However developing my argument on
the abstract nature of clearance the unit of clearance is volume per
unittime for instance mls/minute. This is very theoretical cause it
is impossible to clear the plasma or serum or urine completely of a
particular drug per unit time.
In practice it is not very accurate hence it absolutely an abstract
concept.
And coming to Biopharmaceutics there are several factors that affect
the elimination of drugs from the body besides clearance and this
factors are well documented in all text books of Biopharmaceutics.
Clearance alone cannot determine the elimination of drugs from the
body there are other Biopharmaceutic factors like protein binding,
deactivation by the gastric acid,First pass effect,solubility of the
active principle in fats ,design of the dosage form etc
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The following message was posted to: PharmPK
Dear Sidney,
You wrote:
> The issue is does elimination determine clearance or
>clearance determine elimination?
OK. The answer is simple: clearance (i.e. the capability
of the body to eliminate drugs from the body by means of
biotransformation, renal excretion and other routes, as
pointed out by Bill Jusko) determines the rate of
elimination. The rate of elimination is determined by (1)
drug concentration, as the driving force, and (2) the
capability of the body to eliminate drugs. In short:
Rate of elimination = Clearance x Concentration
I fully agree with Nick Holford that there is no other way
to see this relationship.
> With reference to pharmacokinetics total body clearance
>is Kel.V where kel is the elimination rate constant and
>V is the apparent volume of distribution of drug.From
>here it is crystal clear that elimination determines
>clearance.
I totally disagree. It has been explained earlier by Nick
Holford and other that the equation 'clearance is Kel.V'
is mathematics, and no pharmacokinetics, since it does not
make clear the cause and the result. The concept
'clearance is Kel.V' is definitely the worst
misunderstanding of pharmacokinetics, as has been pointed
out repeatedly by Nick Holford and others. For example,
the textbook of Shargel and Yu is completely wrong at this
point.
>However developing my argument on the
>abstract nature of clearance the unit of clearance is
>volume per unittime for instance mls/minute. This is
>very theoretical cause it is impossible to clear the
>plasma or serum or urine completely of a particular drug
>per unit time.
> In practice it is not very accurate hence it absolutely
>an abstract concept.
Again, I totally disagree. There is nothing abstract in
the concept of clearance. Your theoretical argument
obscures the aforementioned 'crystal clear' concept of
clearance.
> And coming to Biopharmaceutics there are several factors
>that affect the elimination of drugs from the body
>besides clearance and this factors are well documented
>in all text books of Biopharmaceutics. Clearance alone
>cannot determine the elimination of drugs from the body
>there are other Biopharmaceutic factors like protein
>binding, deactivation by the gastric acid,First pass
>effect,solubility of the active principle in fats
>,design of the dosage form etc
Of course clearance is dependent on several factors like
plasma protein binding. I don't know which textbook you
are citing, but clearance is not dependent on deactivation
by the gastric acid, first pass effect, solubility of the
active principle in fats, and design of the dosage form.
There is no reason why the concept of clearance should be
different in different areas.
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
Hans,
Clearance determines elimination, no doubt. On that you and Nick and I
agree.
However, the original question was whether clearance determines
metabolism.
After all the discussion and consideration, I now believe it does not.
IMHO, clearance is a result of metabolism and other forms of loss. It
is a
composite measure of the capacity of the system to remove drug from a
unit
volume of blood or plasma in a unit time -- no matter how many
mechanisms
are involved. It does not cause the mechanisms, but is a result of them.
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.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Dear Walt,
This discussion was a mix of terminology and fundamental
pharmacokinetics.
The major point is that we agree on the latter.
> IMHO, clearance is a result of metabolism and other forms of loss.
> ...
> It does not cause the mechanisms, but is a result of them.
I agree. Clearance might be considered as a result of the underlying
mechanisms, e.g. metabolism, glomerular filtration, or active
excretion. And
as a result of these mechanisms, a drug is eliminated from the body.
This
view is in line with the concept that clearance is a measure of the
capability to eliminate drugs. Here 'metabolism' refers to the
process of
enzymatic conversion of a drug, and not to the resulting elimination.
So we
should not say, for example, 'elimination is the sum of metabolism and
excretion' (thus mixing up cause and result), but 'total elimination
is the
sum of elimination by metabolism and excretion', or 'total clearance
is the
sum of metabolic clearance and renal clearance'. It is quite
difficult to
use the right terms, and perhaps my statements will again result in a
thread
of messages. But writers of textbooks should take care of precise
terminology!
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
[This has been an interesting discussion. I have a problem with a
statement above that might be 'definition' related.
"Here 'metabolism' refers to the process of enzymatic conversion of a
drug, and not to the resulting elimination."
To me metabolism IS one of the elimination processes. Once the drug
is metabolised it is no longer in the body and can longer exert a
pharmacological action. It is a different chemical. It may revert
back to the original drug (chemical) by some process but that would
be beyond our current attempts to simplify the discussion...
Consequently for me:
"elimination is the sum of metabolism and excretion"
and
"total elimination is the sum of elimination by metabolism and
excretion"
are the same because 'elimination' and 'total elimination' mean the
same thing...
For my students I am trying to tell them that elimination (total) is
the result of many pathways including metabolism and excretion.
Therefore
kel = ke + km1 + km2 + ...
OR
CL = CL(k) + CL(h)1 + CL(h)2 + ...
Is this wrong or just a (slightly) different definition.
Talking of review: Another thread talked about models for hepatic
clearance. I've put together a couple of applets estimating CL(H)
according two models and thereby estimating C versus time. Not quite
finished and I think I might add oral versions where F = 1 - E.
Comments?
http://www.boomer.org/c/p4/ja/Fig1702/Fig1702.html
and
http://www.boomer.org/c/p4/ja/Fig1703/Fig1703.html - db]
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The following message was posted to: PharmPK
s.o.o
What was raising alot of dust was pretty simple with reference to
Pharmacokinetics elimination is sum of metabolic and excretion
reactions in the body. However clearance boils down to a theoretical
calculated figure (ugandan English). So for clearance to determine
elimination of drugs is a bit outrageous
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HI,
Maybe a good approach to understand clearance is to go back to the
very original biochemistry, here specifically enzymatic kinetics;
CL=Vmax/km. CL now is a measure of the two characteristics of the
enzyme kinetics; the total capacity (related to the total amount the
enzymes available to the compounds, and the intrinsic turnover
efficiency), and the affinity. All these are determined by the nature
of the compound-enzyme interactions. From this point of view, it is
easy to understand that concentrations have nothing to do with
clearance (let's discuss it within the context of linearity). CL is
more commonly used rather than elimination rate because it is
concentration-independent parameter. CL could be viewed as the volume
cleared off the compound per unit time, but this does not mean that
the body really wants to do in this way. There may be an analogue to
the concept of CL from physical chemistry; what is enthalpy, H=U+PV?
H is derived so that people can use it as a convenient tool, but in
nature, H does not exist as an entity and has no easily interpreted
meaning. The concepts of internal energy (U) and the mechanical work
(PV) are the more fundamantal terms to understand H . Here so CL;
Vmax and Km is easier to be visualized to understand CL.
Huadong Tang
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The following message was posted to: PharmPK
Hi,
Could someone suggest useful references for calculating Clmax for drugs
showing positive cooperativity. I checked out a few by Houston,
etc...but
i am confused as to the calculations involved and experiments for
estimating alpha, beta, and other interaction parameters.
Any suggestion is highly appreciated!
Thanks,
Shringi Sharma
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