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The following message was posted to: PharmPK
Dear all
I have a basic doubt regarding half life. Ideally
speaking half life is a parameter dependent on K so
half life determined by i.v. and oral route should be
same. But if a drug gives different half lives on
i.v. and oral administration (same dose and identical
formulation) what might be the reason.
Thanks in advnance
Nitin Mehrotra
Research Scholar
Pharmacokinetics and Metabolism Division
CDRI Lucknow
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The following message was posted to: PharmPK
Dear Nitin,
Although you have not mentioned it, I am assuming that your half-life is
longer after oral compared to iv administration. Longer half-live after
oral administrations means that the time for the drug to be absorbed is
longer than the time for it to be eliminated, or k for absorption is
smaller than k for elimination. Since the drug cannot be eliminated
before
it is absorbed, the longer half-life you get after oral administration
reflects the absiorption half-life. This phenomenone is also known as
flip-flop.
I am not sure if I understood your statement of "identical formulation".
Since you are discussing iv and oral administrations, the formulations
cannot be identical.
I hope it helped.
Toufigh Gordi
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The first reasons for a different half-life estimated after the i.v.
and oral administration that come to my mind are as follows:
1) The sampling interval was not long enough and therefore the
estimated kel is the results of a combination of the elimination and
absorption processes.
2) The "flip-flop" mechanism, when the absorption process is slower
than the elimination. In that case the slope of the terminal linear
portion of the semilogarithmic plot will represent the absorption rate
constant and not the elimination.
In both cases the half-life estimated after the oral administration
should be larger than that estimated after the i.v. administration.
Another possibility is a lack of specificity of the analytical assay.
As a results the concentration levels measured after the oral
administration may be "contaminated " with contributions from some
metabolite(s).
I hope this help,
radu
Radu D. Pop
Director Biopharmaceutics
Pharma Medica Research Inc.
966 Pantera Drive
Mississauga, Ontario
Canada, L4W 2S1
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The following message was posted to: PharmPK
Nitin,
This can be an artifact caused by the limit of quantification if the
oral
bioavailability is not close to 100%. In this case the half-life after
oral
administration will appear to be shorter than after IV. If the
bioavailability is OK then this may be an example of "flip-flop"
kinetics
where Ka is less than Ke. In this case the half-life after oral
administration may appear to be longer than after IV. There are other
possibilities that relate to the experimental design. Hope this helps.
Brian Sadler
Strategic PK Consulting, LLC
bsadler1.-at-.nc.rr.com
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Dear Nitin,
The half-life is the interval of time necessary for the concentration to
decrease 50% in the range of time where the function c(t) is
approximately
logarithmic. The value of the half-life is equal to the slowest
identified
eigenvalue of c(t) and may be equal to the turnover rate of one of the
compartments the drug goes through, or to no compartments of the system.
I have tried to explain it on page 46 of "Foundations of
Pharmacokinetics"
published by Kluwer/Plenum. If you like I could send you a copy of the
relevant chapter by e-mail.
Greetings,
Aldo
Aldo Rescigno
14767 Square Lake Trail N.
Stillwater, MN 55082-9278
Phone: +1-651-430-9738
Fax: +1-651-430-9739
E-mail: rescigno.aaa.earthlink.net
resci001.-at-.tc.umn.edu
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Assuming no errors in collecting and analyzing data, and linear
pharmacokinetics, a longer half-life for an oral dose means that
absorption is still going on after Tmax. So it may look like the drug
is clearing, but absorption is "holding the curve up" and offsetting
some of the clearance. This creates a longer effective half-life, but
in actuality, the elimination is the same (again, assuming linear
kinetics). Once there is no absorption, the plasma concentration-time
curve should describe the clearance in the same manner as the iv curve.
On the other hand, if you have saturable clearance, then you might see
a shorter half-life for the oral dose if the concentration levels are
lower, because the saturable process is less saturated and so is able
to clear the drug at a faster (relative) rate.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
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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