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We normally tend to believe that higher the protein binding, longer
would be the t1/2. But with 90% serum protein compound, can the half
life be around 1 hour.
Any possible explanations I am looking for.
Sandeep
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The following message was posted to: PharmPK
Dear Sandeep
Remember that half life is a hybrid PK parameter and reflects not only
volume of distribution (highly dependent on protein binding) but also
clearance .
T1/2= 0.693 .Vd / ClB
I don't think that you should consider that higher the protein binding longer
would be the half life. Since having two drugs with the same clearance, the
one having the highest protein binding, will have the lowest Vd and then,
the shortest half life.
Fabiana Landoni
Prof. Dra Maria Fabiana Landoni, PhD
Catedra de Farmacologia.
Facultad de Ciencias Veterinarias
Universidad Nacional de La Plata
FAX +54-221-425-7980
Calle 60 y 118 cc 296
(1900) La Plata.
ARGENTINA
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The following message was posted to: PharmPK
You are just considering protein binding in the central compartment.
How about tissue binding in the extravascular compartment? Also, if
clearance is relatively high in comparison to the volume of
distribution, the half-life can be short. Moreover, if the drug has
high extraction ratio and therefore high clearance, protein binding will
not influence clearance significantly.
Sam Rebello
Pilot PK - DMPK/US
Aventis Pharmaceuticals
(908)-231-4108
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For high E drug with CL defined by Q, the T 1/2 will change because Fup only
affects Vss; however, for low E drugs, CL = Fup*CLint, and the change in Vss
via changes in Fup will offset the changes in CL and therefore no change in
half life.
Art Straughn, Pharm.D.
Professor and Director
Drug Research Laboratory
University of Tennessee
874 Union Ave
Suite 5P
Memphis, TN 38163
E-mail: ASTRAUGHN.-at-.UTMEM.EDU
Phone: (901) 448-6033
Fax: (901) 448-6940
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The following message was posted to: PharmPK
Dear Sandeep,
As you Know, the half-life depends on both clearance
and volume of distribution. t1/2 =3D (Vd*0.693)/CL.
Only the unbound fraction of the drug will be
distributed and metabolized, so the increase in plasma
protein bound fraction of a given drug will be
accompanied by a decrease in its volume of
distribution and a decrease in its clearance.
The indirect impact of the protein binding on the
half-life will depend on which of the two parameters
(CL and Vd) will be more influenced by the change in
binding.
=46or drugs where the clearance is flux-dependent, it is
insensitive to changes in plasma protein binging, and
the alteration in plasma protein binding will affect
the half life mainly through the volume of
distribution (a positive relation ship)
The inverse situation is found with drugs with a
capacity-dependent clearance, in this case the
clearance will be more sensitive to the protein
binding change and the change in the fraction bound
will affect the half-life mainly through the
clearance.( a negative relation ship between CL and pp
binding) and in this case an increase in pp binding
will produce a decrease in CL and consequently an
increase in t1/2.
Sincerely
Youssef Hijazi
H=F4pital neurologique et neurochirurgicale
UNITE DE PHARMACOLOGIE CLINIQUE
d=E9partement de dosage de m=E9dicaments et de Pharmacocin=E9tique
B.P. Lyon Montchat 69394 Lyon Cedex 03-FRANCE
Tel: 04 72 35 72 45
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The following message was posted to: PharmPK
Sandeep,
You need to re-consider your beliefs. Consider the case of aspirin, 99%
protein bound and yet a relatively short half-life, then there is morphine
only 60% or so bound to proteins and yet it has a half-life longer than
aspirins. Of all factors to be considered in determining half-life, protein
binding should not be considered predictive at all. In any event as other
responses have made clear, you should really not be focusing on half-life as
it is a hybrid parameter but on clearance and volume and their underlying
components.
Dennis Bashaw, Pharm.D.
Team Leader, Pharmacokinetics
US Food and Drug Administration
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[A few replies - db]
From: bangarurk.-at-.drreddys.com
Date: Thu, 19 Apr 2001 11:03:04 +0530
To: david.at.boomer.org
Subject: Re: PharmPK Protein binding and half-life
The following message was posted to: PharmPK
Yes it is possible. Because protein binding and elimination half -life are
not always correlated. This happens with many drugs and for exapmple
ibuprofen, nefazodone bindings more than 90% but half-lives are 1-4 hours
only.
---
From: "ukneqas"
Date: Thu, 19 Apr 2001 09:10:17 +0100
To: david.-a-.boomer.org
Subject: Re: PharmPK Protein binding and half-life
The following message was posted to: PharmPK
Weak binding?
Heat instability?
---
From: "Thomas A Torda"
Date: Thu, 19 Apr 2001 18:15:16 +1000
To: david.at.boomer.org
Subject: Re: PharmPK Protein binding and half-life
The following message was posted to: PharmPK
Is it not the case that loosely bound drugs behaviour, such as partitioning
within the body or elimination is not profoundly affected by binding? Tight
boud drugs are another matter. Most drugs are loosely protein bound.
Tom Torda UNSW Oz
---
From: "Xiaofeng Wang"
Date: Thu, 19 Apr 2001 08:11:43 -0400
To: david.-at-.boomer.org
Subject: RE: PharmPK Re: Protein binding and half-life
The following message was posted to: PharmPK
The amount that a drug is bound to protein is an equilibrium issue, while
half life is a kinetic issue. A drug can still have a very short half-life,
even though the amount of bound can reach 99% (as mentioned by Dennis
Bashaw), as long as the elimination rate is faster than that of the
drug-protein binding.
xiaofeng
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The following message was posted to: PharmPK
Sandeep,
Equations describing the relationship between drug half-life
and protein binding for hepatically metabolized drugs with low
or high extraction ratios are(1):
1) high extraction ratios
T1/2= .693*[Vb + (Fb/Ft)*Vt]/[Q]
2) Low extraction ratios
T/2= .693*[Vb + (Fb/Ft)*Vt]/[Fb*Cli]
[The above are derived from T1/2= .693*Vd/Cl]
Equation 1 suggests that an increase in free fraction in the
blood would tend to increase the Vd of a drug with a high extraction
ratio, and thus increase the T1/2. Equation 2 suggests the an increase
in free fraction in the blood of a drug with a low extraction ratio
would tend to increase the Vd, but also would tend to increase the
systemic clearance, so that the change in half-life would be a function
of the relative increase in Vd versus clearance.
Observations on the effects of decreases in protein binding on
half life have found the changes in half life are dependent on the
size of the volume of distribution, and whether the drug is a low
or a high extraction drug(2). Drugs with high extraction ratios and large
Vd's undergo an increase in half-life with decrease in plasm protein
binding (increase in Fb in equation 1). Whereas drugs with low extraction
ratios and small Vd's undergo a decrease in half-life with decreases
in plasma protein binding (increase in Fb in equation 2).
This would suggest that the effect of protein binding on half-life
is an interplay between the effect on the drug's volume of distribution
and the drug's clearance, such that a decrease in half-life with decreased
protein binding would only be expected in a low extraction drug with
a small Vd. In the later case, the increase in clearance predominates
over the increase in Vd (equation 2).
Mike Leibold, PharmD, RPh
ML11439.-at-.goodnet.com
References
1) Gibaldi,M., Perrier, D., Pharmacokinetics 2nd ed, New York,
Marcel Dekker 1982
2) Benet, L., et al, Pharmacokinetic Basis for Drug Treatment, New York,
Raven Press 1984
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)