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Hi, All
I am working on PK of a compound whose oral absorption is very fast as
also the elimination. However, when I inject that compound Sub -
cutaneously the AUC obtained is lower than the oral route AUC. Also the
Cmax obtained with Sub cut route is lower than the oral route.
However, in my efficacy studies the Sub - cut route is giving better
protection as compared to Oral route.
Can anyone throw some light on this.
Yati Chugh Ph.D
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Hi Yati:
It's nice to see your mail.
Regarding your problem,One has to see the following:
1. Vehicle in Sc and oral (suspension or solution)
2. Type of molecule structurally and its solubility
3. secondly you might have observed low concentrations for prolonged
time intervals may benificial rather than looking at high cmax and
more exposure by oral route. Whatever observations you are finding is
common and no surprise. You also check whether your IC50 or EC50
in-vitro if any values for this compound under question.
Hope this info may be useful.
best wishes
natraj
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Yati,
The different time courses by the two routes may mean you are seeing
the phenomenon of schedule dependence. It is also possible that the
drug has an antagonistic action at higher concs. Schedule dependence
is probably more common.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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[A few replies - db]
Date: Mon, 26 Jul 1999 08:17:00 +0100
From: cawello.-at-.schwarzpharma.com
Sender: cawello.aaa.schwarzpharma.com
Reply-To:
Organization: Schwarz Pharma Group
To: PharmPK.at.boomer.org
Subject: re: PharmPK SC vs PO - efficacy vs availability
Importance: Normal
X-SMF-Hop-Count: 1
Form: Reply
Text: (23 lines follow)
Dear Yati,
With a very fast absorption of the drug after oral administration you will
'see' then plasma concentrations profile of the transport process of
distribution within a multicompartment model. Using the subcutaneously route
of administration you reduce your 'view of molecules within the central
compartment' down to the transport of elimination, only. With this you can
have different AUCs (lower after sc than oral adm.) implementing a higher
number of molecules in the process of binding to the target receptor. If you
use your logtransformed concentration data vs time, you can judge your
problem and may be you can reduce the view to the AUCs effected by the one
compartment model. Than you can compare the AUCs and I am sure you will find
a similar relation as your pharmacodynamic parameters?
*********************
Willi Cawello, Ph.D.
Clinical Pharmacology
Schwarz Pharma AG
Alfred-Nobel-Str.
D40789 Monheim am Rhein, Germany
Cawello.aaa.schwarzpharma.com
***********************
---
Date: Mon, 26 Jul 1999 09:40:26 +0200 (IST)
X-Sender: ahoffman.-at-.cc.huji.ac.il
To: PharmPK.at.boomer.org
From: "Dr. Amnon Hoffman"
Subject: Re: PharmPK SC vs PO - efficacy vs availability
Dear Yati,
I assume that your findings are related to the pharmacodynamic profile of
the drug you use. If Emax is reached at relative low concentrations than the
higher Cmax do not contribute to higher magnitude of effect. There are many
examples similar to your finding. For instance the s.c. administration of
erythropoietin produces considerably better effects than IV administration.
You may find more about it in A. Hoffman Advanced Drug Delivery Reviews 33
(1998) 185-199.
Amnon
Dr. Amnon Hoffman
Dept. of Pharmaceutics
School of Pharmacy
The Hebrew University of Jerusalem
P.O.Box 12065
Jerusalem 91120
Israel
Tel: 972 2 6758667
Fax: 972 2 6436246
Email ahoffman.aaa.cc.huji.ac.il
---
Date: Mon, 26 Jul 1999 08:21:00 -0400
To: PharmPK.at.boomer.org
From: shoaf.at.clinpharm.niaaa.nih.gov
Subject: Re: PharmPK SC vs PO - efficacy vs availability
Depot effect.
e.g. Trimethoprim is formulated as a suspension in Tribrissen(r), a
trimethoprim/sulfadiazine mix for veterinary use. TMP is rapidly absorbed
following oral administration and fairly rapidly eliminated. The
therapeutic effectiveness of the mixture is determined by the half-life of
TMP. Upon subcu administration, the TMP is slowly absorbed from the
injection site, appropriate concentrations are maintained for much longer
as elimination is dependent on the absorption rate because it is the rate
limiting factor.
I have references if you need them.
Susan Shoaf, Ph.D.
Acting Chief
Unit of Pharmacokinetic Studies
NIAAA/LCS
10 Center Dr., MSC-1256
Bethesda, MD 20892-1256
301-496-4936
shoaf.-at-.clinpharm.niaaa.nih.gov
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Would it be possible that your compound is precipitating at the site
of sub cut injection and make its release extended. Were you able to
calculate the clearance after sub cut injection?
Nabil
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