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Dear PharmPK members:
Can we expect a slow absorbing drug to be eliminated fast. If so, what
could be the reason(s).
I would appreciate any comments on this.
Best Regards,
Kasiram Katneni
Victorian College of Pharmacy,
Monash University.
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[A few replies - db]
From: "Willi Cawello"
Date: Thu, 22 Aug 2002 07:45:23 +0200
To: david.-at-.boomer.org
Subject: Re: PharmPK Absorption vs Elimination
Status: RO
Dear Kasiram Katneni,
sometimes the elimination rate constant is greater than the absorption
rate. Then we have the so called 'flip-flop' occurs. The terminal phase
of a concentration-time curve then reflects the absorption process and
not (as is usually the case) the elimination of the active component.
Such a flip-flop model may be observed for drugs that are very rapidly
eliminated, or for dosage forms that slowly release drug in an apparent
first order fashion. Physicochemical properties may be the reason for a
slow absorption rate constant.
Best Regards,
Willi Cawello
Willi Cawello, PhD
Senoir Scientist Pharmacokinetics
SCHWARZ BIOSCIENCES GmbH
Alfred Nobel Str. 10
D40789 Monheim am Rhein, Germany
willi.cawello.-a-.schwarzbiosciences.com
+02173 481480
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From: "Doc, Frederic"
Date: Thu, 22 Aug 2002 02:23:49 -0400
To: david.-at-.boomer.org
Subject: RE: PharmPK Absorption vs Elimination
Status: RO
Kasiram,
I think so. Elimination rate would then follow the absorption rate (it can
not be bigger).
One reason for this is drug solubility. If your drug is poorly soluble then
its dissolution in the GI tract is the issue for absorption. Once it is
available the liver can transform it (conjugaison) into a soluble metabolite
with renal tropism and fast elimination.
Regards,
Frédéric
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From: "Sam, A.P. (Tom)"
Date: Thu, 22 Aug 2002 10:01:21 +0200
To: david.-at-.boomer.org
Subject: RE: PharmPK Absorption vs Elimination
Status: RO
Dear Sir,
Elimination can be slower than absorption and
and show up as a reversal ("flip-flop") of the
two phases in a graphical presentation. In such a
case first the elimination phase is shown followed
by the absorption phase.
The situation especially occurs in case of
extended-release preparations, but can also
be related to intrinsic properties of the drug
such as poor solubility and/or poor permeability.
Tom Sam
Regulatory Affairs
NV Organon
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From: "Mutasim Al-Ghazawi"
Date: Thu, 22 Aug 2002 12:15:49 +0200
To: david.-at-.boomer.org
Subject: Re: PharmPK Absorption vs Elimination
Status: RO
Dear Kasiram,
the answer is YES. and this is what we call Flip-Flop Kinetics.
among the reasons are
1- the drug is of very low solubility
2- the half-life is very short (isoproterenol)
3- the drug is formulated as an extended release product
hope this will be of some help
Mutasim Al-Ghazawi, Ph.D
Faculty of Pharmacy
University of Jordan
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From: "Saghir, Shakil (S)"
Date: Thu, 22 Aug 2002 06:43:38 -0500
To: david.-a-.boomer.org
Subject: RE: PharmPK Absorption vs Elimination
Status: RO
Absorption and elimination are two independent variables. Absorption, e.g.,
from GI tract, is dependent upon the dissolution of the drug, its passage
through the membrane and in some cases the ability of a drug to bind with
efflux transporter proteins etc. etc. However, once drug is absorbed, it can
be eliminated rapidly or slowly depending upon the characteristic of the
molecule; it can be rapidly metabolized and eliminated or in some cases
eliminated as a parent compound or can sequestered in some tissue and "hang
around" for quite some times.
Hope this will help.
Shakil A. Saghir, M.S.P.H., Ph.D.
Senior Research Toxicologist
The Dow Chemical Co.
1803 Bldg., Midland, MI 48674
Email: ssaghir.aaa.dow.com
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Dear Kasiram,
If a compound induces its own metabolism you may get
fast elimination.
Rostam
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Dear Kasiram
The best example of "flip-flop" Kinetics is Metformin.
Drugs which have window of absorption and slow
dissolving may show this phenomena. You can understand
this by studying PK of Metformin. It is a drug that
shows non-linear PK due to saturation of absorption
process.
Best wishes
Swaroop
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