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Dear All,
I am profiling two compounds with interesting PK properties
- Both are plasma protein bound (>98%),
- the target organ for efficacy is liver (hepatocytes)
- Liver being the target organ we obtained a distribution
profile in liver. Both compounds are highly extracted in liver after
oral dosing (in-vivo tissue distribution, 100 folds AUC over
plasma)There is no disease animal model of efficacy for this
indication, so target organ conc. are critical.
- One compound has high hepatic clearance and gets eliminated
within 8 hrs after oral dosing.
- Second compound with such high hepatic extraction is not
cleared easily and its t1/2 in liver is as high as 20 Hrs. All studies
were done in rat.
-
Question -
If a drug is plasma protein bound, with high hepatic extraction, can
it still translate into in-vivo efficacy as the target is in
intracellular hepatocyte ?
What could be the reason for a compound to be metabolically stable
(Liver t1/2 =>20Hrs) although it is highly extracted in liver?
My Best,
Vishal Pendharkar
Scientist, Pharmacology,
CombinatoRx, 11 Biopolis Way, Helios #08-05/06,
Singapore 138667
Email: vpendharkar.-at-.combinatorx.com
http://www.combinatorx.sg
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Vishal,
The answer to your first question is "yes". If the compound is having
higher binding affinity to the target receptor than that of plasma
proteins, plasma protein binding becomes irrelevant for in vivo
efficacy.
To answer your second question, you might want to have a look at
Clearance and volume of distribution (Vd) values. Is that compound
having high Vd? Whats the chemical nature and properties
(lipophilicity etc.) of compound?
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Satya Jadhav wrote:
> The answer to your first question is "yes". If the compound is having
> higher binding affinity to the target receptor than that of plasma
> proteins, plasma protein binding becomes irrelevant for in vivo
efficacy.
I don't know what the original question was but I dont agree with the
implication of the answer that if the affinity to the target receptor
was lower than plasma proteins that this would be relevant for in vivo
effectiveness.
The affinity of a drug to plasma proteins (or any other inactive binding
site) is irrelevant to the effectiveness of a drug. It makes no
difference whether the affinity to plasma proteins is higher or lower.
It is only unbound drug concentration that is important for drug
effects.
Please read this paper:
Benet LZ, Hoener B. Changes in plasma protein binding have little
clinical relevance. Clinical Pharmacology & Therapeutics. 2002;71(3):
115-21.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.at.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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You beat me to it Nick: the unbound drug interacts with the "target".
Interestingly I am just about to embark on the topic of the Benet et al
paper as part of a lecture series to pharmacy students.
Regards,
David
David Foster, PhD
Lecturer
Sansom Institute
School of Pharmacy and Medical Sciences
Room P4-08
City East Campus
University of South Australia
Adelaide SA 5000
Email: david.foster.-a-.unisa.edu.au
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Vishal, what do you mean by second compound having high hepatic
extraction? What is the basis of determining this, are you making this
statement based on the liver to plasma ratio? If yes, then I do not
think that the term high extraction would be appropriate here, but
rather distribution into the liver is probably more
pharmacokinetically correct statement. What was the plasma t1/2
compared to that of the liver for the second compound. Are they
similar or different?
Regarding your question
If a drug is plasma protein bound, with high hepatic extraction, can it
> still translate into in-vivo efficacy as the target is in
intracellular
> hepatocyte ?
Why not, the invivo efficacy depends upon the Kd of the compound for
the receptors and in terms of the free concentration the compound if
potent enough should be ok. Also you mentioned that the second
compound distributes quite well into the liver (what is the % bound in
liver tissue). Further do you know if the second compound's protein
binding is linear or nonlinear at the concentrations achieved?
> What could be the reason for a compound to be metabolically stable
(Liver
> t1/2 =>20Hrs) although it is highly extracted in liver?
Again, by high extraction is probably not applicable here as
extraction refers to the fraction/% of drug entering the liver which
is removed irreversibly by the liver. In your case a high liver to
plasma ratio suggests distribution. So if this is true, then a
compound can undergo distribution into the liver due to a high
partition coefficient but not necessarily fully metabolized. It could
be that saturation of the enzymes might be also occurring.
Neil
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Nick,
I agree with your view about the implication of my original answer but
actually I meant to say that plasma protein binding is not always
restrictive for the pharmacodynamics of drug. In certain cases total
rather than the free drug is responsible for the effect.
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Satya
> answer but actually I meant to say that plasma protein
> binding is not always restrictive for the pharmacodynamics
> of drug. In certain cases total rather than the free drug is
> responsible for the effect.
Interesting.
Can you provide a drug example (with reference) in which the drug is
bound to albumin (or alpha1-acid glycoprotein) and for which the total
(bound and unbound drug) is responsible for effect.
Regards
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull.at.otago.ac.nz
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The following message was posted to: PharmPK
Satya,
Satya Jadhav wrote:
> I agree with your view about the implication of my original answer
but
> actually I meant to say that plasma protein binding is not always
> restrictive for the pharmacodynamics of drug. In certain cases total
> rather than the free drug is responsible for the effect.
Would you please explain what restrictive means for pharmacodynamics?
Would you please tell me the examples of drugs where total concentration
rather than unbound concentration is responsible for the effect? (with
references to the original literature describing the work)
Thanks
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.at.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Steve,
> Can you provide a drug example (with reference) in which the drug is
> bound to albumin (or alpha1-acid glycoprotein) and for which the
total
> (bound and unbound drug) is responsible for effect.
I think propofol is thought to be an example. It's been a while since I
worked with it and I do not have references at hand (I can try to dig
them out later), but it is highly bound to albumin, and highly
lipophilic. It has very fast onset of action (in the brain), and I
recall that it was hypothesized (I do not remember whether it was proven
though) that the amount that crossed BBB correlated better with total
rather than unbound drug.
Regards,
Katya
--
Ekaterina Gibiansky
Senior Director, PKPD, Modeling & Simulation
ICON Development Solutions
Ekaterina.Gibiansky.at.iconplc.com
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The following message was posted to: PharmPK
Katya,
Gibiansky, Ekaterina wrote:
> I think propofol is thought to be an example. It's been a while
since I
> worked with it and I do not have references at hand (I can try to dig
> them out later), but it is highly bound to albumin, and highly
> lipophilic.
I tried to find some supporting data for propofol PD depending on total
plasma conc. There was nothing I could find with Google Scholar, Google
or PubMed. I did found a reference describing blood and plasma binding
of propofol (Mazoit et al. 1999):
> "Results Propofol free fraction in blood was 1.2--1.7% at total
> concentrations ranging from 2.80 to 179 ?m (0.5 to 32 ?g ml^-1 ).
> Fifty percent was bound to erythrocytes and 48% to serum proteins,
> almost exclusively to human serum albumin. In the clinical range of
> concentrations (0.5--16 ?g ml^-1 ) 40% of the molecules bound to
> erythrocytes are on the red blood cells membranes. No binding to
> lipoproteins occurred and binding to ?_1 -acid glycoprotein was less
> than 1.5%"
The paper discusses the PK and PD consequences of propofol binding in
some detail but it asserts quite clearly that it is expected that only
the unbound concentration is important for effects.
Jean Xavier Mazoit KS. Binding of propofol to blood components:
implications for pharmacokinetics and for pharmacodynamics. Br J Clin
Pharmacol. 1999;47(1):35-42.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-a-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Nick, Steve,
I think that there is a risk of oversimplifying by insisting that only
unbound drug in plasma can exert effects. For example, it is still not
clear whether or not albumin can act as a carrier for bound drug; it is
thought that albumin is endocytosed and recycled by FcRn, so this could
play a part, if rather slow.
In any case, the concentration of drug in blood or plasma, whether bound
or unbound, is usually a surrogate marker for the concentration of drug
at the site of action. When a drug is used in approximate steady state
conditions, this surrogacy is a reasonable approximation, because at
steady state, the unbound concentration in plasma is in EQUILIBRIUM with
and EQUAL to the unbound concentration in every tissue except where drug
is being absorbed and where drug is being cleared. Here, I agree with
you.
But what about when the drug is not near steady state or equilibrium?
In ALL situations, the UNBOUND concentration is the driving force for
NETT transfer of drug between compartments, but it is not the only
source of drug. Blood takes 5 seconds to pass through the human brain
(cf 0.5 seconds in mouse) and 10 seconds or more to pass through the
sinusoids of the liver, with a fair proportion of the blood having
considerably longer residence time. In these times, if there are
near-sink conditions in the organ, such as shortly after a dose, the
initial free pool of drug in plasma can be considerably depleted,
leading to replenishment from the bound pool of drug. It is unusual for
the dissociation of drugs from plasma proteins to have time-constants
longer than 0.1 seconds, so the off-rate does not help much.
There are drugs which are 90% protein bound in plasma yet 80% extracted
in a single pass through the liver. This is the real cost of high PPB -
it hits the potency of your drug but does not protect it so well from
hepatic clearance because sink conditions can be maintained in the liver
through metabolism, so you have to increase the dose. And don't forget
"binding" (partition) in red blood cells - they can be another pool on
"bound" drug.
Propofol is an exceptional drug in many ways!
By the way, the argument in drug discovery is how seriously to take PPB.
Some organisations set a limit, say <95%; others just scratch their
heads! The original question from Vishal Pendharkar was about drugs
where liver is the site of action, and where one drug is cleared faster
than the other. It could be caused by transporters (efflux is very
sensitive to passive permeability as well as affinity for pumps), or one
drug considerably exceeding its Km inside the hepatocytes. Do you have
hepatocyte turnover or just microsomes? Watch out for cholestasis if
canalicular pumps are involved.
Regards.
Ted
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Katya
> > Can you provide a drug example (with reference) in which
> the drug is > bound to albumin (or alpha1-acid glycoprotein)
> and for which the total
>
> > (bound and unbound drug) is responsible for effect.
>
> I think propofol is thought to be an example. It's been a
> while since I worked with it and I do not have references at
> hand (I can try to dig them out later), but it is highly
> bound to albumin, and highly lipophilic. It has very fast
> onset of action (in the brain), and I recall that it was
> hypothesized (I do not remember whether it was proven
> though) that the amount that crossed BBB correlated better
> with total rather than unbound drug.
Again - we would need to see the data to see whether this is true.
Essentially one would expect very lipophilic drugs to cross the BBB
very fast and in this setting be dragged off the protein. Hence the
protein just acts as a transport medium in the blood. What we need to
see is evidence that (1) the bound drug passes across the BBB intact
and (2) the bound drug acts at the site of action?
Steve
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Katya
> > Can you provide a drug example (with reference) in which
> the drug is > bound to albumin (or alpha1-acid glycoprotein)
> and for which the total
>
> > (bound and unbound drug) is responsible for effect.
>
> I think propofol is thought to be an example. It's been a
> while since I worked with it and I do not have references at
> hand (I can try to dig them out later), but it is highly
> bound to albumin, and highly lipophilic. It has very fast
> onset of action (in the brain), and I recall that it was
> hypothesized (I do not remember whether it was proven
> though) that the amount that crossed BBB correlated better
> with total rather than unbound drug.
Again - we would need to see the data to see whether this is true.
Essentially one would expect very lipophilic drugs to cross the BBB
very fast and in this setting be dragged off the protein. Hence the
protein just acts as a transport medium in the blood. What we need to
see is evidence that (1) the bound drug passes across the BBB intact
and (2) the bound drug acts at the site of action?
Steve
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The following message was posted to: PharmPK
Nick, Steve,
> Again - we would need to see the data to see whether this is true.
> Essentially one would expect very lipophilic drugs to cross the BBB
> very fast and in this setting be dragged off the protein. Hence the
> protein just acts as a transport medium in the blood. What we need
to
> see is evidence that (1) the bound drug passes across the BBB intact
> and (2) the bound drug acts at the site of action?
I did not say that propofol crosses BBB while still bound to albumin, I
agree that the molecule is dragged off it. But in this case presumption
that only unbound fraction measured in plasma (2%) will lead to the
effect is not correct.
Below is the reference and the abstract:
S. Dutta, Y. Matsumoto, A. Muramatsu, M. Matsumoto, M. Fukuoka and W. F.
Ebling. Steady-state propofol brain:plasma and brain:blood partition
coefficients and the effect-site equilibration paradox. British Journal
of Anaesthesia, Vol 81, Issue 3 422-424, 1998.
"Based on volume-flow relationships, CNS agents that are highly lipid
soluble (log octanol-water partition coefficient > 2) are expected to
have equilibration half-times (T1/2 kE0) that are proportional to brain
solubility. Propofol, the most lipophilic anaesthetic in clinical use,
has T1/2 kE0 values of 1.7 and 2.9 min in rats and humans, respectively,
compared with an expected value of at least 8 min. As a first step in
exploring this discrepancy between observed and predicted values, we
determined the steady state brain:plasma and brain:blood partition
coefficients in rats after a 4-h infusion of propofol. Brain:plasma and
brain:blood partition coefficients were 8.2 (SD 1.6) and 3.0 (0.5),
respectively. T1/2 kE0 predictions based on brain: blood partitioning in
rats are more in agreement with the observed equilibration half-time,
suggesting that drug bound to the formed elements of blood participates
in the uptake and transfer of propofol to its effect site."
Regards,
Katya
--
Ekaterina Gibiansky
Senior Director, PKPD, Modeling & Simulation
ICON Development Solutions
Ekaterina.Gibiansky.-at-.iconplc.com
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Nick, Steve,
My statement was based on the following references which might be
useful for further discussion.
1. P.H. Van der Graff et al, JPET 290: 702-709, 1999
2. P.H. Van der Graff et al JPET 283: 809-816, 1997
3. Tanaka & Mizojiri JPET 288: 912-918, 1999
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As a little note to this thread:
Abraxane, which is a suspension of albumin-bound paclitaxel particles,
is thought to be taken up via transcytosis across endothelial cells
mediated by albumin-receptors.
Best regards,
Frederik Pruijn
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
E-mail: f.pruijn.aaa.auckland.ac.nz
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Dear all -
For an example where the free fraction "hypothesis" does not seem to
work, you may want to see:
"Unexpected relationship between plasma protein binding and the
pharmacodynamics of 2-NAP, a CCK1-receptor antagonist"
Br J Clin Pharmacol 63:5 618-622.
V. P. Gerskowitch, J. Hodge, R. A. D. Hull, N. P. Shankley, S. B.
Kalindjian, J. McEwen & J. W. Black
James Black Foundation, 68 Half Moon Lane, London, and Drug
Development (Scotland) Ltd, Ninewells Hospital & Medical School,
Dundee, UK
Conclusions
The pharmacological effect of a drug is usually considered to be
determined by its free concentration. However, the complete inhibition
of CCK-8S-evoked gallbladder contraction by a free plasma
concentration of 0.04 mm 2-NAP was much greater than would have been
predicted from simple drug-receptor occupancy theory and cautions
against the general use of free concentration of drug for predicting
pharmacological effect.
--
My comment - Of course, one can always argue the presence of an active
metabolite, slow disassociation rate, and a bunch of explanations for
the conclusion stated by the authors.
Dario
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Hi,
Satya Jadhav wrote:
> The answer to your first question is "yes". If the compound is having
> higher binding affinity to the target receptor than that of plasma
> proteins, plasma protein binding becomes irrelevant for in vivo
efficacy.
Nick Holford replied:
> I don't know what the original question was but I dont agree with the
> implication of the answer that if the affinity to the target receptor
> was lower than plasma proteins that this would be relevant for in
vivo
> effectiveness.
Satya Jadhav then wrote:
> > I agree with your view about the implication of my original
answer but
> > actually I meant to say that plasma protein binding is not always
> > restrictive for the pharmacodynamics of drug. In certain cases
total
> > rather than the free drug is responsible for the effect.
Nick Holford replied:
> Would you please explain what restrictive means for pharmacodynamics?
> Would you please tell me the examples of drugs where total
concentration
> rather than unbound concentration is responsible for the effect?
(with
> references to the original literature describing the work)
Quite a few people responded to this and I'd like to congratulate Ted
Parton for
putting his finger on an important question - are we discussing an
equilibrium
state or a transient pharmacokinetic delivery phenomenon?
My comment and question to Satya was posed under the assumption of an
equilibrium state because there was no mention of pharmacokinetic
transients.
Satya provided 3 references to support his view:
van der Graaf et al. 1997, 1999 describe estimates of adenosine A1
agonist affinity at binding sites mediating lipolysis and heart rate
slowing and these are an attempt to obtain affinity estimates under
equilibrium assumptions. The only thing I could find that might be
pertinent to the discussion was on p 707 of the 1999 paper. The authors
noted that pKa (negative log of agonist dissociation equilibrium
constant i.e. affinity) for lipolytic effects based on unbound conc was
similar to the pKa for heart rate effects based on total blood conc but
I could not find where it said "total rather than the free drug is
responsible for the effect". I would be grateful is Satya would help me
understand how the van der Graaf papers support this assertion.
Tanaka & Mizojiri 1999 describe a study of the permeability of the blood
brain barrier. This is a PK study with no pharmacodynamics and thus not
relevant to the issue of whether total drug concs or unbound drug concs
determine drug effects. It does show however that plasma protein bound
drug may be extracted in the cerebral circulation which of course has
been known for decades based on hepatic extraction studies. BBB
permeability changes associated with plasma protein binding were shown
to be a function of perfusion rate and thus due to a non-equilibrium
phenomenon.
Frederik Pruijn mentions another example of albumen aided uptake of
paclitaxel but once again this is PK not PD.
Katya Gibiansky cited a PKPD experiment using propofol in rats
(Dutta et al. 1998). Based on brain:blood partition compared with
brain:plasma partition the authors provide an explanation for the delay
in onset of propofol effects. The factors determining the equilibration
half-life are clearly described in this article and relate to
pharmacokinetic extraction phenomena and not to the relationship between
total conc and unbound conc effects at equilibrium.
Dario Doller provided a clearer example when he cited the study of
Gerskowitch et al. 2007. The authors found 2-NAP, a CCK1 competitive
antagonist, produced inhibition of CCK induced gall bladder contraction.
They claim "simple drug receptor competition theory would have
predicted only 10% and 3% reductions, respectively, by these free
concentrations of 2-NAP against an ED50 dose of CCK-8S.". The
concentration change during the CCK infusion and the conc-effect
relationship for CCK are not described so I dont know how they made this
calculation. The peak (1 h) end infusion 2-NAP total conc was 166 uM
i.e.
unbound conc of 0.214 uM (fu=0.00129). The reported in vitro Kd
(equilibrium
dissociation constant) is 0.72 uM so this would would mean that with 2-
NAP it
would require a 1.3 fold increase in CCK concentration to get the same
effect
(1+[2-NAP]/Kd=1+0.214/0.72=1.29).
This is a non-equilibrium experiment with much of the important
information
missing to decide if the effect is bigger than expected from the
unbound plasma
conc. However,I agree that the inhibitory effect of 2-NAP does seem
greater than
one would predict from the unbound plasma conc.
So I remain unconvinced that total drug concentrations are responsible
for drug effects in comparison to unbound drug concentrations except for
some special cases when this might appear to be the case because of
pharmacokinetic extraction processes. Such phenomena are not due to
relative affinities of plasma proteins and target receptors (which is
where I joined this thread).
Steve Duffull wishes to support the above remarks and also adds these
2 reasons
why we expect drug effects to be mediated by unbound conc and not
total conc:
1) That the drug receptor interaction is likely to be unbound since
it is
difficult to believe that a drug that is bound to albumin would exist
in the
right conformational state to activate the receptor. But this needs
to be
tested independently.
2) That under equilibrium dynamics unbound drug concentration has
equilibrated
with all tissues and unbound concentrations should be proportional to
the
unbound concentration in the plasma to the value of the partition
coefficient.
(In agreement with Ted Parton's comment.)
These are testable hypotheses in their own right and hence refs
against these
are required to reject the unbound component.
Non-equilibrium kinetics is a completely different kettle of fish
which needs to
be addressed differently.
Thank you all for a stimulating discussion.
Nick and Steve
References
Van der Graaf PH, Danhof M. Analysis of drug-receptor interactions in
vivo: a new approach in pharmacokinetic-pharmacodynamic modelling. Int J
Clin Pharmacol Ther. 1997;35(10):442-6.
Van der Graaf PH, Van Schaick EA, Visser SA, De Greef HJ, Ijzerman AP,
Danhof M. Mechanism-based pharmacokinetic-pharmacodynamic modeling of
antilipolytic effects of adenosine A(1) receptor agonists in rats:
prediction of tissue-dependent efficacy in vivo. J Pharmacol Exp Ther.
1999;290(2):702-9.
Tanaka H, Mizojiri K. Drug-protein binding and blood-brain barrier
permeability. J Pharmacol Exp Ther. 1999;288(3):912-8.
Dutta S, Matsumoto Y, Muramatsu A, Matsumoto M, Fukuoka M, Ebling WF.
Steady-state propofol brain:plasma and brain:blood partition
coefficients and the effect-site equilibration paradox. Br J Anaesth.
1998;81(3):422-4.
Gerskowitch, VP et al. Unexpected relationship between plasma protein
binding and the pharmacodynamics of 2-NAP, a CCK1-receptor antagonist.
Br J Clin Pharmacol. 2007;63(5):618-22.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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The following message was posted to: PharmPK
Dear Dario,
Thanks for the interesting reference, which I wasn't aware of.
As far as I understand it the protein binding experiments in the
article were performed at ambient temperature. Because protein binding
is temperature-dependent and generally (?) decreases with increasing
temperature the authors may have underestimated the fraction free drug
at 37*C.
Best regards,
Frederik Pruijn
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
E-mail: f.pruijn.-at-.auckland.ac.nz
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Imatinib may be more clear example:
Br J Clin Pharmacol. 2006 Jul;62(1):97-112. Population
pharmacokinetics of imatinib and the role of alpha-acid glycoprotein.
Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A,
Rochat B, Eap CB, Henry H, Biollaz J, Buclin T.
Clin Cancer Res. 2003 Feb;9(2):625-32. Alpha1 acid glycoprotein binds
to imatinib (STI571) and substantially alters its
pharmacokinetics in chronic myeloid leukemia patients. Gambacorti-
Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S,
Tornaghi L, Rossi F, Pioltelli P, Pogliani E, Alberti D, Corneo G,
D'Incalci M.
Regards,
Ignacio
--
Ignacio Segarra, Ph.D.
Department Head, Pharmaceutical Technology
Senior Lecturer, Pharmacokinetics
International Medical University
School of Pharmacy
Department of Pharmaceutical Technology
No. 126 Jalan 19/155B, Bukit Jalil
57000 Kuala Lumpur
MALAYSIA
--
E-mail: ignacio_segarra.-at-.imu.edu.my
E-mail: segarra100.-at-.gmail.com
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Hi,
I could not discover what led Ignacio to post to this thread. The
pharmpk archive does not reveal the previous link. (See
http://www.boomer.org/pkin/PK05/PK2005593.html
- a 2005 thread with the identical subject).
Thanks Ignacio for making me look at these paper. I hope that readers
of PharmPK will look carefully at the BJCP paper he cites:
Br J Clin Pharmacol. 2006 Jul;62(1):97-112. Population
pharmacokinetics of imatinib and the role of alpha-acid glycoprotein.
Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A,
Rochat B, Eap CB, Henry H, Biollaz J, Buclin T.
which very clearly and carefully shows that there is no evidence that
plasma protein binding has any effect on the pharmacokinetics of
imatinib when one takes the rational view that only unbound
concentrations are meaningful for understanding dispostion processes
and pharmacodynamics.
Please do not make the mistake in thinking that pharmacokinetics based
on total drug concentrations have any relevance once one can
understand the pharmacokinetics based on unbound concentration.
Nick
[Sometimes the subject line is changed by subsequent posters (which I
try to change back to keep the thread), in other cases someone may
have seen the old posting. I've tried to make commenting on old
postings easy but it can be confusing - db]
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