PharmPK Discussion - Metabolism studies of unstable compounds

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On 13 Dec 2001 at 10:22:26, Chandrani Gunaratna (prema.at.bioanalytical.com) sent the message


The following message was posted to: PharmPK

To the group;

  I am trying to investigate the in vitro metabolism of anti-oxidants.
These compounds, for example silybinin, light sensitive, degrades
considerably at 37C and also not stable at pH 7.4 and very insoluble
in water. Can somebody recommend some measures to study the
microsomal metabolism of such compounds? It will be a great help to
me.

Thank you

Chandrani Gunaratna
Chandrani Gunaratna, Ph.D.
Senior Research Scientist
Bioanalytical Systems
2701 Kent Avenue
West Lafayette, IN 47906
(765)463-4527

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On 17 Dec 2001 at 10:10:52, David Bourne (david.-at-.boomer.org) sent the message

[Two replies - db]

From: "Dave Vowles" 
Date: Thu, 13 Dec 2001 18:13:48 -0000
To: david.-at-.boomer.org
Subject: Re: PharmPK Metabolism studies of unstable compounds

The following message was posted to: PharmPK

Why bother, since enzyme-mediated metabolism may be of  little significance
in vivo ?

Dave

---

From: Alexander.Treiber.aaa.Actelion.Com
Date: Fri, 14 Dec 2001 11:46:31 +0100
To: david.-a-.boomer.org
Subject: Re: PharmPK Metabolism studies of unstable compounds

Dear Chandrani.

this sounds like a quite ambitious undertaking. Among all the
features you describe light sensitivity and poor solubility in
aqueous media still appear the easiest to solve by working under
strict exclusion of light and at low concentrations of the chemical.
Using an appropriately radiolabeled analogue is certainly the most
practical approach. The major issue for the remaining problems is to
clearly differentiate between the products of true metabolism and
those of temperature/pH and possibly matrix-induced degradation.
Practically this means that you will have to perform control
experiments for each and any type of incubation experiment under
exactly the same conditions. Moreover, you will have to keep in mind
that not only your test substance undergoes non-metabolic degradation
but that also the metabolites might be unstable. Vice versa, the
non-metabolic degradation products might undergo metabolism
potentially rendering your product pattern even more complicated.

Best regards
Alex

Alexander Treiber, PhD
Head of Preclinical Pharmacokinetics and Metabolism
Actelion Pharmaceuticals Ltd.
Gewerbestr. 16
CH-4123 Allschwil
Phone: +41-61-487 45 92
FAX: +41-61-487 45 00
E-mail: alexander.treiber.-a-.actelion.com

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