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From: Xiaobing Qian
Date: Thu, 12 Jun 2003 11:59:14 -0700 (PDT)
To: david.-a-.boomer.org
Subject: Vehicle for IV PO PK in mice
The following message was posted to: PharmPK
Dear all, I am look for a
suitable vehicle to perform an iv/PO PK study in mice to assess the oral
bioavailibity of a small molecule compound. This compound has limited solubility
in aquous solution, 7 ug/ml at pH 7.4. I need to stay away from PEG400 because
we found that PEG alone affected some readouts in the model we are interested
in. Could you please recomend some suitable vehicles to use? Please include the
maximal volume/percentage that I can use for these vehicles. Please advice other
issues that I should consider as well. For example, whether I have to use the
same vehicle for iv and PO study?
Thank you very much!
Xiaobing
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From: Xiaobing Qian
Date: Thu, 12 Jun 2003 11:59:14 -0700 (PDT)
To: david.aaa.boomer.org
Subject: Vehicle for IV PO PK in mice
The following message was posted to: PharmPK
Dear all, I am look for a
suitable vehicle to perform an iv/PO PK study in mice to assess the oral
bioavailibity of a small molecule compound. This compound has limited solubility
in aquous solution, 7 ug/ml at pH 7.4. I need to stay away from PEG400 because
we found that PEG alone affected some readouts in the model we are interested
in. Could you please recomend some suitable vehicles to use? Please include the
maximal volume/percentage that I can use for these vehicles. Please advice other
issues that I should consider as well. For example, whether I have to use the
same vehicle for iv and PO study?
Thank you very much!
Xiaobing
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From: "Doc, Frederic"
Date: Mon, 16 Jun 2003 10:09:05 -0400
To: david.-a-.boomer.org
Subject: Re: Vehicle for IV PO PK in mice
The following message was posted to: PharmPK
Dear Xiaobing,
of course you do not need to use the same vehicle iv and po. The strategy is
to get a stable solution as an iv formulation. This means that you should
consider surfactants such as Cremophor EL, Polysorbate 80 or Solutol HS15 at
concentration up to 5% in a pH7.4 phosphate buffer. In case the
solubilization of your active in this kind of vehicle is not high enough you
should also consider a cyclodextrin-based vehicle.
But my advice would be: do not use any cosolvent such as DMSO, PEG or
others. With such a low ph7.4 solubility your active is likely to
precipitate at the injection point and your iv reference for the
bioavailability calculation would be wrong (and you could find that your
drug is bioavailable at a rate much larger than 100% !!!).
Below are some references to help in defining the amount of surfactants and
cyclodextrin to dose in animals. But in the case of the surfactants the
concentration must be kept below the critical micellar concentration.
Hope this helps
Regards
Frederic
References:
Cyclodextrins:
- Pitha , J. and all , Life Sci. , 43 ,493-502 (1988)
- Coussement W. and all , Mins. 5 th Int. Symp. Cyclodextrins ; Duchêne,D.
Ed. ; Editions de Santé : Paris ; pp 522-524 (1990)
Solutol:
- SAFETY EXPERT REPORT FOR SOLUTOL HS 15 Prepared by K.Schilling,December
1994
Cremophor EL:
- Handbook of pharmaceutical excipients.
- Astill B.D. and coll ,Fund. And Appl.tox , 31 , 29 (1996)
Polysorbate 80:
- Ash Michael and Irene. Handbook of pharmaceutical additives. Gower house
(1995)
- Zehe O. and coll J.clin.Periodental 25 , 892 (1998)
- Fukunaga and coll , Jpn. Pharmacol Ther. Vol 25 , suppl 97 271 (S 729)
- Chaturvedi A.K. J. of Applied Tox. Vol 13(3) ,183 (1993)
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The following message was posted to: PharmPK
Dear All,
I have done a oral chronic study in mice with PEG400 as the vehicle.
Mice treated with PEG400 only have lost a lot of weight. Is there
anybody who knows about the long term effect of PEG400 given orally in
mice?
Thank you in advance
Dr Sylvie Le Corre
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The following message was posted to: PharmPK
Dear Sylvie
for toxicological effects as reference source you can see Toxnet at
http://toxnet.nlm.nih.gov/
and a possible reference for long term toxicity of PEG 400 in mice is:
Klugmann FB, Decorti G, Mallardi F, Klugmann S, Baldini L.
Effect of polyethylene glycol 400 on adriamycin toxicity in mice.
Eur J Cancer Clin Oncol. 1984 Mar;20(3):405-10.
Best Regards
Stefano Porzio
Pharmacokinetic & Tox. Dept.
Inpharzam Ricerche SA
Zambon Group
Taverne
Switzerland
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The following message was posted to: PharmPK
Hello Sylvie:
I have no specific information about PEG400 (we tend to use
cyclodextrins
as our favored vehicle -- but not for more than 2 oral doses).
However, I
was curious about your method of oral dosing. I assume you are using
repeated gavage? Have you done repeated dosing of mice with anything
else
-- such as saline, water, etc. -- just to make sure that it isn't the
repeated handling/dosing of the mice that's causing the weight loss
problem? Is food intake and fecal output otherwise OK? Are the mice
going
back to a communal cage, or to isolation, or to a special enclosure
such as
a metabolic cage? I guess my point is that there are several potential
possibilities for weight loss.
Best Wishes,
Candice Kissinger
Senior V.P. Research
BASi
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Dear All, PEG400 being a non-ionic surfactant had an effect on the GI
tract.
upon chronic administration, the most important symptom to b observed is
diarrhoea. If diarrhoea was evident, that would b the main cause of
loss of
weight. Pelase advise me if my thinking is wrong,thanks,Jagannath Kota
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The following message was posted to: PharmPK
I believe PEG 400 is not a non-ionic surfactant but a semi-polar solvent
which dissolves a lot of organic compounds. Mostly it is used in
combination
with other solvents as water. This is because in a pure state it causes
a
very high osmotic pressure which will tend to decrease by attraction of
water into the GI tract and cause diarrhoea.
When PEG is linked to a more lipophilic compound as a fatty acid or a
fatty
alcohol the derivative becomes amphiphilic and surface active. Then the
increase in solubility of water insoluble compounds is due to
solubilization.
Kind regards
Prof. Dr. R. KINGET
Dorpsstraat 139
B-3060 BERTEM
Belgium
http://www.farm.kuleuven.ac.be/pharbio/vraagbox.htm
Tel /Fax 32 - (0)16 - 49 01 49
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The following message was posted to: PharmPK
PEG-400 can cause diarrhoea in rodents.
Mr.Rabi Sankar Bhatta
Junior Research Fellow
c/o Dr.G. K. Jain
Central Drug Research Institude,
Post Box- 173,Chattar Manzil Palace,
Lucknow (U.P)
India
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