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Dear Group,
It has been observed that the -SH group present in thiol containing
NCE can non-specifically form a disulfide with endogenous substances
possessing -SH groups like glutathione (GSH) or cysteine (CYS) in
blood. Although several derivatization methods have been reported
that prevents ex-vivo conversion by blocking the -SH group present in
endogenous GSH or CYS, no method is available till date to mimic an
in-vivo condition. Insight into the literature reveals that those
disulfides may be reduced to -SH by reductase enzymes, in-vivo. In
this connection, I seek your invaluable clarification on following
doubts...
1. How to go about the Pharmacokinetics/Bioanalysis of those
thiol-containing NCEs to mimic an in-vivo situation?
2. Although biological thiols are abundant, can we use drugs
that can deplete cellular GSH viz., Ethacrynic acid (Diuretic) to
minimize non-specific in-vivo conjugation of thiol containing NCEs
with GSH?
3. Will it be worthy considering thiol containing NCEs as they
pose major analytical challenge during drug development?
Thanks in advance.
Regards,
Syed Mustafa,
Drug Metabolism & Pharmacokinetics,
Orchid Research Laboratories Ltd,
Plot No: 476/14, O M Road,
Sholinganallur, Chennai -600 119.
INDIA
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The following message was posted to: PharmPK
Hi Syed,
I have worked more than one decade on biological thiols, such as GSH,
Cys
and Protein-SH groups. From this experience and from all reviews on the
biological function of these compounds, I have to warn you urgently to
think about depletion of biological thiols in vivo! These compounds are
life-saving in terms of preventing oxidative stress reactions and
damage by
reactive metabolites. In fact, there are some drugs known - such as
paracetamol - which in high doses deplete biological thiols with
dramatic
consequences particularly for the liver.
If you just want to mimic in vivo situation of disulfide reduction,
you may
use an enzymatic system of GSSG, glutathione reductase and an
NADPH-regenerating system (e.g. glucose-6 phosphate, glucose-6-phosphate
dehydrogenase and NADP+). However, this will probably not completely
mimic
in vivo, since reduction of disulfides may also occur via ascorbic
acid or
other thiols.
For more in depth information please consider reviews on biological
thiols
or GSH.
Hope this helps
Best regards
Dieter
--
Dr. Dieter Gallemann
Senior Scientist
Merck KGaA
Institute of Drug Metabolism and Pharmacokinetics
Am Feld 32
D-85567 Grafing
Germany
Tel.: +49 (0) 8092-7008-11
Fax: +49 (0) 8092-7008-7011
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