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Hi,
I'm very confused about the relationship between hepatic extraction
rates and metabolism. I keep coming across statements to the effect
that as the hepatic extraction ratio approaches 1, then clearance
approaches hepatic blood flow and rates of metabolism do not then
affect clearance. I hope I stated that appropriately. I can
understand this from a very simplistic equation perspective as I have
found delineated in the PharmPK archives. What I don't understand
then is what contributes to extraction? Can one predict what will
lead to a high extraction rate for compounds? Is this just some
feature of a compound that allows it to be readily excreted in urine?
I hope I'm not more confused than I think I am! I'm really not
looking for a deep understanding of the derivation of the equations
regarding clearance, just an understanding of what hepatic extraction
means. The other will have to wait :)
Thanks so much,
Noelle
[I have a little bit of this on http://www.boomer.org/c/p4/c17/
c1704.html - db]
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Noelle,
This is a very weird statement:
> "I keep coming across statements to the effect
> that as the hepatic extraction ratio approaches 1, then clearance
> approaches hepatic blood flow and rates of metabolism do not then
> affect clearance. I hope I stated that appropriately."
Clearance determines the rate of metabolism not the other way around!
It is true that hepatic blood flow is one of the determinants of
hepatic clearance. If the intrinsic clearance of the liver (i.e. the
metabolizing enzyme capacity) is high then almost all the drug
entering the liver may be metabolized as it passes through the liver.
This means most of the drug entering the liver is extracted. Hepatic
extraction ratio is the fraction of drug entering the liver that is
extracted.
The hepatic extraction is determined both by the blood flow and by
the intrinsic clearance. If blood flow is low then this gives the
liver plenty of time to extract drug and extraction ratio will be
high. On the other hand if the blood flow is high then drug can rush
through the liver without being given a chance to be metabolized. If
clearance is low then less drug is metabolized per unit time and
extraction will be low. If clearance is high then more drug is
metabolized per unit time and extraction will be high.
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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Nick,
I have to take issue with your statement that "Clearance determines
the rate
of metabolism not the other way around!".
Because drug can be cleared by a variety of mechanisms, including
metabolism, it would seem that metabolism is a contributing factor to
clearance.
For example, according to Ritschel, "Clearance is the hypothetical
volume of
distribution in ml of the unmetabolized drug which is cleared per
unit of
time(ml/min or ml/h) by any pathway of drug removal (renal, hepatic, and
other pathways of elimination)."
When metabolism constitutes all of clearance, then it would seem more
correct to say that the metabolic rate determines the clearance.
Best regards,
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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Thank you to all who replied to my simplistic question, including David
Bourne's suggestion to look to his class lectures. My statement was
indeed weird. I now have a much clearer understanding of the concept.
Please forgive the naiveity of someone still learning the basics.
You
all have consistently been very helpful (and patient!) with my
questions.
Noelle
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Walt,
You are mixing up elimination rate with clearance.
The pharmacokinetic definition of clearance is:
Elimination Rate = Concentration x Clearance
Rischel's definition is dimensionally correct but of no use in
understanding what clearance really is.
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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This is a multi-part message in MIME format.
> Nick Holford wrote:
>
> Clearance determines the rate of metabolism not the other way around!
Nick:
I agree with you if here you mean by "clearance" the intrinsic clearance
of the eliminating organ tissue. Otherwise, I would argue that the rate
of metabolism (divided by the total or free concentration) defines the
total or free clearance, respectively.) To avoid a circular argument, I
suggest that the rate of elimination (mass/time) is determined
(additively) by the intrinsic clearances:
-for metabolized/transported drugs, the Michaelis-Menton equation. At
low drug concentration relative to Km, Vmax/Km is the inverse of
intrinsic clearance
- for filtered drugs, the physicochemical equation for filtration, which
under physiologic conditions collapses to GFR*Fu*Conc
I hope you are enjoying tomorrow.
Paul
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
777 Highland Avenue
Madison WI 53705-2222
Tel 608.263.2496
Fax 608.265.5421
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One should be careful with the terminology, since metabolic clearance
does not determine the rate of metabolism. In fact it corresponds to
the proportionality constant between that rate and the amount (or
concentration) of drug. The extraction ratio and clearance concepts
are complementary but distinct. The former relates to the efficiency
of the clearing process, while the latter relates to its efficacy.
For example, a drug with a high hepatic extraction ratio may have its
hepatic clearance accounting for a small percentage of the total
plasma clearance. Conversely, a drug may only have the metabolic
pathway for elimination, but with a low efficiency due to a small
extraction ratio. All four combinations of the two factors are
plausible.
--
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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It does sound counter-intuitive. Taking this relationship to the
extreme, when (metabolic) clearance is zero, wouldn't it be correct to
say that the drug is not cleared because it is not metabolized, not the
other way around?
Regards,
Andrew
Andrew Volosov, PhD
Assoc. Director, DMPK
Inotek Pharmaceuticals
978-232-9660
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Nick,
I've checked a couple other references in addition to Ritschel and I
find:
Gabrielsson & Weiner: "Clearance is the volume of blood or plasma
that is
totally cleared of its content of drug per unit time (vol/time)."
Gibaldi & Perrier: ". . . clearance is the ratio of elimination rate
to the
drug concentration entering the organ" and "The total clearance of
drug from
the body almost always involves more than one organ."
I don't see that I'm confusing clearance and elimination - the two have
different units.
I will admit that my understanding of the word clearance could be
wrong, but
as I understand it at this moment based on the references I have,
clearance
is a consequence of various pathways that cause drug to be removed
from the
blood. I assume when we say clearance with no modifiers it is
understood to
be total clearance, vs hepatic clearance, renal clearance, etc.
From my current understanding, saying clearance determines
metabolism rate
is like saying the gas mileage on my car determines the flow through the
injectors - it is exactly the opposite.
Best regards,
Walt
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Walt,
Gabrielson & Weiner make the same mistake as Ritschel. They simply
define clearance in terms of its units without saying what it really is.
None of the references you cite say this "as I understand it at this
moment based on the references I have, clearance is a consequence of
various pathways that cause drug to be removed from the blood".
Clearance is NOT a consequence of various pathways that cause drug to
be removed.
Elimination IS a consequence of various pathways that cause drug to
be removed.
This is why I say you are mixing up clearance and elimination.
The following formula is a causal relationship and expresses the
pharmacokinetic definition of clearance used by Gibaldi & Perrier:
Elimination rate = Concentration x Clearance
Both the right hand quantities determine i.e. are the cause of the
elimination. Period.
> From my current understanding, saying clearance determines
> metabolism rate
> is like saying the gas mileage on my car determines the flow
through the
> injectors - it is exactly the opposite.
>
It seems you think clearance is an analogue of gas mileage. I dont
get the analogy.
I can understand that metabolism (mass/time) and flow through
injectors (volume/time) are both rates but there the analogy stops.
Once again you seem to confuse elimination (mass/time) with clearance
(volume/time).
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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Nick,
So many confused authors - makes you wonder how these books ever get
published. ;o)
My analogy was intended to be one of (somewhat) similar cause and
effect.
The rate of gasoline consumed through the injectors results in gas
mileage -
the gas mileage doesn't cause the flow rate through the injectors.
Metabolic rate(s) + renal filtration + biliary secretion of parent +
exsorption of parent through the gut wall + parent drug exhaled from
lungs +
parent drug lost through perspiration + drug eliminated via any other
route
all add up to produce total clearance, do they not?
I'm not at all confusing elimination and clearance. Just because you can
write an equation
elimination = concentration * clearance
(mass/time = mass/volume * volume/time)
doesn't establish whether any of these are causes or effects in the most
basic sense. Concentration is a time-dependent consequence of volume and
(rate in - rate out). It doesn't cause rate in or rate out, or volume
for
that matter. Clearance does not cause rate in or rate out, either,
but is
simply a way of expressing rate out in terms of volume units cleared per
unit time.
If clearance is not zero at any instant in a system, it is because at
least
one underlying mechanism is either converting parent drug to
metabolite, or
allowing parent drug to get out of the system. That's the cause - how we
express the rate at which it happens (i.e., the effect) is up to us - as
mass/time or volume cleared/time.
I would like to hear the logic behind saying that clearance causes
any of
these mechanisms to happen. It may seem like semantics, but I don't
think it
is. Clearance is a fundamental concept that I thought I understood
well, and
if I don't, I want to.
I don't see that you've explained the rationale for your statement that
"Clearance determines the rate of metabolism not the other way around!"
Walt
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Dear Colleagues,
It is always a question of terminology, isn'it?
By definition, the amount of drug which is eliminated by the liver R
cleared per unit of time can be expressed as follows:
R cleared (mg/h)= Eh * Rin (mg/h)
where Rin represents the amount of drug entering the liver per unit
of time and Eh the hepatic extraction ratio
Here Eh, the hepatic extraction can be expressed as the ratio CLh/Qh
where CLh is the overall hepatic clearance and Qh, the liver blood flow.
I think that everything is clear based on mass balance equations that
define all processes involved in elimination.
From mass balance equations:
Cp,u x u1 - Chep,u u-1 - Chep,u x um - Chep,u x u2 = 0
Cp,u x u1 - Chep,u (u-1 + um + u2) = 0
Chep,u = (Cp,u x u1)/(u-1 + um + u2)
where u1, u-1, u2 and um are the uptake, efflux, metabolism and
excretion rates of the ligand, Chep,u and the Cp,u are the unbound
concentration of the drug in hepatocytes and plasma in the
environment of the transporter(s) and/or metabozing enzyme(s).
Generally, the relationship between the initial transport or
metabolic rate (u0) and the unbound concentration (Cu) is expressed
as follows:
u0 = (Vmax x Cu) / (KM + Cu)
The intrinsic clearance CLint which reflects the intrinsic capacity
of the system to transport and/or metabolize a drug is defined as the
proportionality constant between u0 and Cu as described by the
following equation:
CLint = u0 / Cu = (Vmax) / (KM + Cu)
Taking passive diffusion component and active transport processes
into account, the transport and metabolism rate can be expressed as
follows:
u1 = Pdif,uptake x Cp,u + [(Umax x Cp,u) / (KU + Cp,u)]
u-1 = Pdif,efflux x Chep,u + [(Emax x Chep,u) / (KE + Chep,u)]
u2 = Pdif,excretion x Chep,u + [(Bmax x Chep,u) / (KB + Chep,u)]
um = [(Vmax x Chep,u) / (KM + Chep,u)]
where Umax, Emax, Bmax and Vmax are the maximum uptake, efflux,
excretion and metabolism rates; KU, KE, KB, and KM are the free
concentrations at half-maximum velocity (M); Pdif,uptake, efflux and
excretion are the non specific uptake, efflux and excretion
clearances (passive diffusion).
All these equations can be expressed using Permeability surface area
product PS, which is defined by PS (L/h) = Pdif + Clint
The overall intrinsic clearance can be therefore be influenced by
each of these processes,
i.e., CLint,all = f ( v1, v-1, vm, v2)
The above equations show that the concentration of the drug within
the liver is related to all processes determining the hepatobiliary
transport and metabolism. In this context, CLint,all includes not
only metabolism, but also transport processes and membrane
permeability. Therefore, overall hepatic CL is not exclusively
determined by metabolic clearance.
Furthermore, since the rates of metabolism, excretion and efflux are
based on the free concentration of the drug, such representation
makes clear both the independence of the four main processes, and the
fact that any one of them may be the overall rate-controlling process.
A number of different theoretical compartmental models can be used to
describe hepatic clearance in terms of the parameters mentioned
above. The most frequently used models are the well-stirred model,
the parallel tube model and the dispersion model. However, these
models were developed to best fit the data and allow an estimation of
hepatic clearance. Such models represent approximations of liver
physiology, share a number of assumptions and have to be chosen
carefully in function of the drug characteristics for an accurate
estimation of the clearance.
With 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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