Back to the Top
I have been studying the acyl migration profiles of several drug
compounds for a new discovery project. I have seen very interesting
data and would like to ask your view regarding this.
Sample preparation and some inportant observations....
- Drug compounds and control compounds are incubated with liver
microsomes (human, dog, monkey), UDPGA and alamethacin for 0, 30 and
60 minutes.
- At 0 minutes I do not see any formation of acyl glucuronides and
three to four isomers are seen at 30 and 60 minute time points.
- 1-o-acyl glucuronide was identified by reaction with B-glucoronidase
- Method is specially designed to allow separation of acyl migrated
isomers. Acyl glucuronidated species are monitored using LC/MS/MS.
- Determination of covalent binding is not possible due to lack of
instrument capability.
- My control compound (Ramatroban) does not show any acyl migration
whereas my drug discovery compounds show acyl migrated species.
- Parent compound shows single peak.
My question is how to interpret these data --
- Do I assume that compounds that form acyl migrated isomers will be
able to bind to proteins and cause potential toxocity?
- Why I do not see acyl migration for Ramatroban?
Your input in this is very valuable and all responses are appreciated.
Thanks very much
Sue
Back to the Top
Please read our review 'Acyl Glucuronide Reactivity in Perspective -
Biological Consequences': Chemico-Biological Interactions, 145,
117-137 (2003).
Kind regards
Ron
Back to the Top
Ron,
Thanks for the reference. Can you please comment on my experiment and
observations? How would you interpret the data? I appreciate your
insight view regarding this.
Thank you
Sue
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Acyl migration and liver toxicity" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)