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The following message was posted to: PharmPK
Dear all
Sorry to bother you all but I am stuggling with this......
The plasma clearance of a compound is approximately 10-fold
greater than mouse hepatic blood flow. Is this very unusual?
Does this suggest extensive hepatic metabolism?
Extrahepatic metabolism? Another mechanism?
The urinary excretion of the compound is minimal
All suggestions very welcome
Thanks very much for your help
Nicola Smith
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The following message was posted to: PharmPK
Hello,
From what I have learned and seen, usually this happens if the
compound undergoes significant degradation/metabolism in blood itself.
You might want to check that.
I don't remember any reference for this but I am sure there are
several drugs with parallel behavior in humans and any basic p'kinetic
book should have this.
Pravin
Pravin Jadhav
Ph.D. Student
Drug Metabolism Research Group, VCU
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[Two replies - db]
From: Toufigh Gordi
Date: Tue Feb 18, 2003 2:47:59 PM US/Central
To: david.-at-.boomer.org
Subject: Re: PharmPK High plasma clearance
Reply-To: Toufigh Gordi
The following message was posted to: PharmPK
Dear Nicola,
Since liver cannot metabolize more drug that comes in, it is unlikely
that a 10-fold greater CL is due to hepatic metabolism (I am assuming
your estimation of hepatic CL is based on iv data).
There might be other sites of elimination for your compound (e.g. lungs
or blood).
Toufigh Gordi
---
Date: 18 Feb 2003
From: walt.-at-.simulations-plus.com
Is this after iv dosing? Have you measured parent drug and
metabolite(s) in feces?
One possibility (if the compound is not highly bound to plasma
proteins) is exsorption into the gut. The intestinal tract can provide
a significant pathway for drug to escape the system - under the right
conditions.
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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The following message was posted to: PharmPK
Dear Nicola,
When the plasma clearance is this high (10 fold of the
hepatic blood flow) this may suggest drug metabolism
or degradation in the plasma/blood.
There are several examples for drug metabolism in the
blood. For example organic nitrates are metabolized
by the esterase enzymes present in the blood, this is
in addition to the hepatic metabolism.
Regards
Mohsen Hedaya, Pharm.D., Ph.D.
College of Pharmacy
Tanta University
Tanta - Egypt
Phone: +20 10 176 8641 +20 40 333 1779
Fax: +20 40 334 8643 e.mail: mhedaya.-a-.e-pharmacokinetics.com
Web site: www.e-pharmacokinetics.com
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[Two replies - db]
From: Pravin
Date: Tue Feb 18, 2003 11:42:07 PM US/Central
To: david.-at-.boomer.org
Subject: Re: PharmPK Re: High plasma clearance
Reply-To: Pravin
The following message was posted to: PharmPK
Dr. Woltosz,
I am just wondering if you were pointing towards involvement of
transporters, P-gp, MRP1/2, which can potentially extrude significant
amount in the intestine? But is it possible to have 10-fold increase
because of transporter intervention?
I am thinking even if it gets kicked out into the gut, some fraction
would eventually come back and clearance value would be slightly
complicated/contaminated.
Then, if we assume Nicola's compound is an ideal substrate for these
transporters, would there be any bioavailability issues?
I guess I have asked too many questions but I am just curious!
Thanks in advance
Pravin Jadhav
---
From: Andrew.Volosov.-at-.ucb-group.com
Date 19 Feb 2003
Dear Nicola,
The simplest explanation would be that your compound is extensively
bound to red blood cells, with high blood/plasma ratio. In this case
you simply have much of your drug discarded after centrifugation, when
you separate plasma. Another possible explanation would of course be
metabolism in whole blood, as has already been mentioned in this
thread. No other metabolic pathway can explain that kind of clearance,
since liver is the most highly perfused organ. Moreover, clearance 10
times higher than hepatic blood flow would also be 2-3 times higher
than cardiac output - no "normal" metabolic pathway can make up for
this. But I would say blood/plasma partitioning is the first thing to
check.
Hope this helps.
Andrew Volosov
UCB Research
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At 02:03 PM 2/19/2003, Pravin wrote:
I am just wondering if you were pointing towards involvement of
transporters, P-gp, MRP1/2, which can potentially extrude significant
amount in the intestine? But is it possible to have 10-fold increase
because of transporter intervention?
Not necessarily - drug that is not subject to carrier-mediated
transport (e.g., propranolol) can be exsorbed into the gut lumen from
an iv dose (Fick's law - drug moves across membranes from high
concentration to low concentration - when the concentration in the
blood is higher than in the gut wall epithelial cells, drug moves into
those cells - then when the concentration in the epithelial cells is
higher than in the lumen, drug crosses into the lumen and begins to
transit downstream).
If it is a substance that is unstable in the lumen, it could degrade
before having a chance to be absorbed back into the intestinal wall
(which also happens with propranolol - the absorption, that is, not
degradation).
I am thinking even if it gets kicked out into the gut, some fraction
would eventually come back and clearance value would be slightly
complicated/contaminated.
Sure can! But with a proper model and good data, you can account for
such behavior and predict it with reasonable accuracy.
Then, if we assume Nicola's compound is an ideal substrate for these
transporters, would there be any bioavailability issues?
I'm not sure how to interpret your question. For an iv dose, we
normally assume BA = 100%, regardless of what happens once the drug is
in the system.
I guess I have asked too many questions but I am just curious!
Not at all - it is a fascinating area!
My explanation is only one of several good ones I've seen here - it
could even be a combination of all of them. Hopefully, one is dominant
and can be gleaned from sufficient data.
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.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Dear Nicola,
As has been pointed out before (see PharmPK entry of Iñaki F. Trocóniz
08.09.2001) the first thing to do is check the partitioning of the drug
into blood cells (blood/plasma ratio). If a drug enters e.g. red cells,
then the plasma concentration is lowered. Therefore plasma AUC is
lower, CL
appears higher. It can even be many fold the blood CL. Please do not
compare plasma CL with any physiologic blood flows unless the
blood/plasma
ratio equals one. In effect we can consider the blood cells as a
"tissue"
or compartment, which is not always measured.
Please also note that there are many pharmaceuticals where the
blood/plasma
ratio is not a constant due to specific binding sites in the blood
cells. A
good example is cyclosporin. The distribution to blood cells can even
take
some time (minutes), which leads to interesting drug properties
following
oral absorption as the fraction in plasma in the portal vein during the
absorption phase can be higher than in the systemic circulation.
If after all this, the blood CL is higher than hepatic blood flow, then
all
the other suggestions should be examined.
Best regards, Phil.
Philip Lowe
Head of Preclinical Modelling
Novartis Pharmaceuticals AG
CH-4002 Basel
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