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19th February 2013 @ 06:41

Glutathione Trapping Study for OSM-S-35 



CDCO_MMV_OSDD_13_001_Met ID.xlsx
CDCO_MMV_OSDD_13_001_Met ID.pdf


We’ve run the glutathione trapping study for OSM-S-35 in the presence of metabolic activation (i.e. human microsomes). We also included a search for other potential metabolites formed. A number of metabolites were detected, mainly oxygenated species (mono, bis and tri-oxygenated metabolites) with the predominant metabolite (based on peak area and assuming similar response factors for each metabolite) arising from likely hydroxylation of the pyrrole substituted benzene. In the presence of GSH-EE, adducts were observed both in the presence and absence of metabolic activation. The results are summarised in the attached file. Please let me or Sue know if you have any questions or comments

Attached Files
CDCO_MMV_OSDD_13_001_Met ID.xlsx
CDCO_MMV_OSDD_13_001_Met ID.pdf
Re: Glutathione Trapping Study for OSM-S-35 by Murray Robertson
19th February 2013 @ 07:02
So am I right in thinking that this is good news for the "near neighbour" series as you are not seeing Michael products?
Re: Glutathione Trapping Study for OSM-S-35 by Alice Williamson
20th February 2013 @ 22:16
Comments above were from Karen White who performed the assay:
Re: Glutathione Trapping Study for OSM-S-35 by Alice Williamson
20th February 2013 @ 22:19
Q&A Between Karen White (KW) and Matthew Todd (MT)

MHT The meaning. Various oxygenated metabolites are proposed, but is their level (after the given time) unusual? Is this compound metabolised relatively quickly?

KW This study was not designed to look at the rate of degradation. We run this under conditions to maximise metabolism so that we can detect metabolites. The previous study (MMV_OSDD_12_001) was conducted to look at the rate of metabolism, and in that study this compound degraded with a moderately fast rate.

MHT The lack of difference in the presence of GSH-EE - does this imply that the double C=C bond of the thiazolidinone is not reacting in the way one might expect it to? i.e. it's not a Michael acceptor? i.e. no "trapping"?

KW I assume you are referring to the comment about GSH not affecting the extent of loss of parent? This comments just means that GSH-EE did not accelerate the rate of degradation but you cannot conclude that there is no trapping. See further down in the table where a conjugate was found for the parent (although the signal was weak) and for +16 and +32 metabolites.

MHT Are there any other results here that are red flags to you, but that I'm missing through inexperience in looking at data of this kind?

KW The fact that GSH-EE conjugates were trapped for the metabolites is not a good sign and suggests that the metabolites could be “reactive” with nucleophiles such as glutathione.
Re: Glutathione Trapping Study for OSM-S-35 by Matthew Todd
25th February 2013 @ 22:22
For the record, the comments immediately above this post were mainly from Sue Charman.