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The following message was posted to: PharmPK
I am presently confronted with a group of compounds showing very high
clearance in the rat (average for 14 compounds is 70% of total cardiac
output, range is 10 to 166%). The clearance of most of these compounds
measured after IV administration exceed hepatic blood flow by over
200%. I
have eliminated plasma instability and blood partitioning as mechanisms.
There is no significant correlation between intrinsic (in vitro) rat
hepatic
microsome clearance and total (in vivo) rat clearance (R^2 = 0.003).
Aqueous
solubility at pH 7.4 is not great (average = 3.5 ug/mL, range = 0 to 9
ug/mL)
but I have seen worse compounds without such high clearance. Nor do I
think
that loss to surface binding is a problem since we have done many in
vitro
studies with good recovery. I have complete faith and confidence in the
bioanalytical work (LC-MS/MS).
I am interested in any explanations for these observations and
suggestions of experimental approaches to identify a mechanism.
Sympathy is
also appreciated [off list - db ;-)].
Richard Knapp
Aventis Pharmaceuticals
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The following message was posted to: PharmPK
Dear colleague,
we as well had a series of high clearance compounds with clearances up
to 3
times the hepatic blood flow. It turned out that liver uptake
transporters
(OATPs) were the reason for that.
What you need is a model expressing those transporters and if the
results
are positive you should look for structures not being transporter
substrates.
I hope this helps.
Best regards,
Bernhard Ladstetter
Bernhard J. Ladstetter, Ph.D.
Head of Global Non-Clinical DMPK
Global Preclinical R&D
Institute of Drug Metabolism and Pharmacokinetics
Merck KGaA
Am Feld 32
D-85567 Grafing
Germany
Phone: +49 (0)8092-700810
Fax: +49 (0)8092-700899
e-mail: bernhard.ladstetter.at.merck.de
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Have you looked at renal clearance? Are these
compounds of a structure that they would be excellent
candidates for the renal ion transport systems? Antibiotics
come to mind most easily.
Dan Sitar
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Hello Richard
Did you compare intravenous versus intraarterial administration to
quantify
the role of lung in the disposition of your compounds?
Venkatesh Atul Bhattaram
CDER, FDA
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Dear PharmPkers,
Surely the highest clearance one can see in the liver is liver blood
flow, regardless of whether there is active uptake or not. You can't
remove more drug than is entering the liver in the first place. Or am I
missing something?
Best Regards
Alex
A.J.MacDonald Ph.D
F. Hoffmann-La Roche Ltd
Pharma Research
Non-Clinical Safety
Modelling and Simulation
PRNS, 70/132
CH-4070 Basel Switzerland
Tel: ++41 61 68 84098
Fax: ++41 61 68 82066
alexander.macdonald.-at-.roche.com
[Lung, blood ? - db]
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Alex: I agree.
If given IV, I would expect even with transporters Cl hepatic would be
limited by hepatic blood flow. On the other hand, if given orally, the
apparent clearance could be much higher than QH. I would expect that
the 3x-hepatic blood flow message above related to oral
administration. If it was given IV, it is very interesting indeed.
Paul
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
777 Highland Avenue
Madison, WI 53705-2222
Tel:(608) 263-2496
FAX:(608) 265-5421
Pager: (608) 265-7000, #7856
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The following message was posted to: PharmPK
Dear Mr. Knapp,
an additional suggestion:
an extremely large vol. of distribution may also mimik a high clearance.
Assume a rapid distribution phase, which is observed by the decreasing
plasma values, followed by concentrationssignificantly to the AUC, in case they had been above LLQ).
regards
H M Bender
Dr. Hans Markus Bender
Merck KGaA
Institute of Drug Metabolism and Pharmacokinetics
Am Feld 32
D-85567 Grafing
[Germany]
Tel: 08092 / 7008-0
Fax: 08092 / 7008-99
e-mail: hansmarkus.bender.-a-.merck.de
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The following message was posted to: PharmPK
Dear Alex and Paul,
of course you are right that PK theory tells us that hepatic clearance
can
not be higher than the hepatic blood flow. However, the example I gave
is
real and what we observed within a series of high clearance drugs (all
dosed iv in the rat) was clearances up to 15 L.kg-1.h-1. What we found
was
that those compounds were very good substrates of both rat and human
OATPs
and that the majority of the dose was excreted rapidly as unchanged drug
with bile. Of course the liver should not extract more than the blood
flow
provides. We did not look into the underlying mechanisms in more detail
as
for obvious reasons we did not further persue these compounds.
Regards,
Bernhard
Bernhard J. Ladstetter, Ph.D.
Head of Global Non-Clinical DMPK
Global Preclinical R&D
Institute of Drug Metabolism and Pharmacokinetics
Merck KGaA
Am Feld 32
D-85567 Grafing
Germany
Phone: +49 (0)8092-700810
Fax: +49 (0)8092-700899
e-mail: bernhard.ladstetter.aaa.merck.de
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The following message was posted to: PharmPK
Fascinating!
Are there examples of experimental or clinical agents that have high
clearance rates that have minimal tissue retention, and animal half
lives predictive for bid or qd dosing?
On a related note, is there a source of info on clinically used (or now
discarded experimental)
agents that have high clearance rates, preferably with correlates of
animal
clearance?
Paul
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
777 Highland Avenue
Madison, WI 53705-2222
Tel: (608) 263-2496
FAX: (608) 265-5421
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At 02:02 AM 8/20/2003, Bernhard.Ladstetter.at.merck.de wrote:
. . . However, the example I gave is
real and what we observed within a series of high clearance drugs (all
dosed iv in the rat) was clearances up to 15 L.kg-1.h-1. What we found
was
that those compounds were very good substrates of both rat and human
OATPs
and that the majority of the dose was excreted rapidly as unchanged drug
with bile.
Perhaps exsorption from the intestinal wall supplements biliary
secretion.
When the (unbound) plasma concentration is high and there is no drug in
the enterocytes, drug will partition into the enterocytes, and,
similarly, thence to the gut lumen. This has been reported with iv
doses of some drugs (propranolol is one I recall).
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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