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The following message was posted to: PharmPK
Dear readers,
I would much appreciate any possible explanations for the set of
results obtained from a study done in rats:
In this study, a dose of a very lipophilic compound (MW: 370) was
administered to rats ( some iv-bolus and others oral).
Blood was extracted and analyzed by HPLC later on and data were
analyzed using Winnolin non compartmental analysis.
Based on our results, this compound had a very short half life
(10 minutes in iv and 13 minutes in oral studies),despite a very high
degree of lipophilicity ( Log P of 2.8) and a fairly high protein
binding (75% protein bound). The clearance for this compound was
calculated to be 1.23(L/Kg/h)in iv study and 1.10(L/Kg/h)in oral
study. The volume of distribution was 0.34 (L/Kg). The rats weighed
between 260 to 290 grams.
The above clearance and volume of distribution seem to be
intermediate to me. Strangley enough, only 3% of the dose was
recovered unchanged in the urine, there were about 10% (of the dose)
glucuronides and sulfate conjugates present in the urine. Based on
the comparison of iv and oral data, the compound was 96% bioavailable!
This compound is a new synthetic nucleoside mimic and does have a
great potential for incorporation into DNA. It is a compound that is
very stable towards hydrolyis, phosphorolysis or any other forms of
degradation.
If this compound were indeed greatly incorporated into the DNA,
shouldn't we have a much greater Vd?
The main question really is:
Where is this compound going to?
Any possible explanations would be greatly appreciated.
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[Two replies - db + where you able to do a mass balance? That is,
account for all the drug]
From: Manish Issar
Date: Sat, 30 Jun 2001 09:12:34 -0400
To: david.-a-.boomer.org
Subject: Re: PharmPK Strange PK results
The following message was posted to: PharmPK
Quoting panteha khalili:
hi
it appears that the drug has a fairly good chances of
converting to glucuronide/sulfates as 10% of the dose
was found in the urine. how about if the drug was
excreted into the bile (mw around 370)and from there it
could have been excreted into the feces. did u perform
the excretion studies of this compound. there could
have been this possibility. hope this helps.
best wishes
manish issar
Department of Pharmaceutics
College of Pharmacy,Box 100494
J.H.Millis Health Center
Unversity of Florida,
Ph:(352)846-2730
Gainesville,
FL-32601
Ph:(352)846-2730
---
From: Stephen Day
Date: Sat, 30 Jun 2001 11:42:21 -0400 (EDT)
To: david.aaa.boomer.org
Subject: Re: PharmPK Strange PK results
The following message was posted to: PharmPK
Did you look in the bile (or feces)?
If you are seeing conjugates in the urine, and ~90% of
the dose is unaccounted for, the rest of the drug may
be excreted into the bile (as conjugate mostly).
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The following message was posted to: PharmPK
Hello
Just two things:
1. How about biliary excretion of ur molecule? I think
u should explore this also because some molecules have
shown predominant biliary excretion in comparison to
urinary.
2. You mention that your drug is also highly stable
(even to P450, I presume) and has not that high volume
of distribution. SInce u are analysing whole blood
(which takes care of intracelluar binding etc) you
might be seeing this value of Vd. If you were to
analyse only plasma then u might see that your Vd will
be quite high which can then give u idea of the actual
intracellular binding etc.
3. Also for molecules like these which incorporate into
intracellular components I think u will need a very
sensitive HPLC assay. I hope you must have done ur
assay on LCMSMS. IF not the parameters what u see might
not be the real ones!!!.
I hope this helps
Atul
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[Two replies - db]
=46rom: "Jean-Xavier.Mazoit.-a-.kb.u-psud.fr"
Date: Mon, 02 Jul 2001 08:40:21 +0200
To: david.-at-.boomer.org
Subject: Re: PharmPK Strange PK results
The following message was posted to: PharmPK
My first explanation is: your drug is in a deep compartment and your assay
is not sensitive enough. If the results are the same with mass spec
detection (or with RIA), I think that you will solve your problem only by
using radioactive compound and see where is the drug.
Good luck !
Jean Xavier Mazoit MD, PhD
Laboratoire d'Anesth=E9sie
Universit=E9 Paris-Sud
=46acult=E9 de M=E9decine du Kremlin-Bic=EAtre
=46-94276 Bic=EAtre France
Tel. (33) (0)1 49 59 67 35-37
(33) (0)1 45 21 34 41 (Hopital)
=46ax (33) (0)1 45 21 28 75
e-mail Jean-Xavier.Mazoit.-a-.kb.u-psud.fr
---
=46rom: "Paul S. Collier"
Date: Mon, 02 Jul 2001 09:09:42 +0100
To: david.-at-.boomer.org
Subject: Re: PharmPK Strange PK results
The following message was posted to: PharmPK
Panteha,
IF the compound is incorporated into DNA by means of COVALENT linkages,
then the compound has been effectively "eliminated" - it is no longer
present in the body as the original chemical entity (this is equivalent
to elimination through the formation of a metabolite). Under these
circumstances, extensive incorporation into DNA would not necessarily
result in a large apparent volume of distribution, in the same way that
elimination by any other route would not necessarily affect Vd.
Paul
Dr P.S. Collier
School of Pharmacy
The Queen's University of Belfast
97 Lisburn Road
Belfast BT9 7BL
N. Ireland, U.K
Tel: +44 (0)28 90 272009
=46AX: +44 (0)28 90 247794
Email: p.collier.aaa.qub.ac.uk
http://www.qub.ac.uk/pha/index.html
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