PMID- 21671437
OWN - NLM
STAT- MEDLINE
DCOM- 20110907
LR  - 20190104
IS  - 1096-9888 (Electronic)
IS  - 1076-5174 (Linking)
VI  - 46
IP  - 7
DP  - 2011 Jul
TI  - Structural identification of SAR-943 metabolites generated by human liver 
      microsomes in vitro using mass spectrometry in combination with analysis of 
      fragmentation patterns.
PG  - 615-24
LID - 10.1002/jms.1930 [doi]
AB  - SAR-943 (32-deoxo rapamycin) is a proliferation signal inhibitor via interaction 
      with the mammalian target of rapamycin (mTOR). Most importantly, SAR-943 has 
      improved chemical stability compared to rapamycin (sirolimus) and is currently 
      under investigation as a drug coated on coronary stents. It was the goal of this 
      study to identify the SAR-943 metabolites generated after incubation with human 
      liver microsomes using high-resolution mass spectrometry (MS) and MS/iontrap 
      (MS(n)) and comparison of fragmentation patterns of the metabolites with those of 
      SAR-943 and other known rapamycin derivatives. Our study showed that SAR-943 is 
      mainly hydroxylated and/or demethylated by human liver microsomes. The structures 
      of the following metabolites were identified: O-demethylated metabolites: 
      39-O-desmethyl, 16-O-desmethyl and 27-O-desmethyl SAR-943; hydroxylated 
      metabolites: hydroxy piperidine SAR-943, 11-hydroxy, 12-hydroxy, 14-hydroxy, 
      23-hydroxy, 24-hydroxy, 25-hydroxy, 46-hydroxy and 49-hydroxy SAR-943; 
      didemethylated metabolites: 16,39-O-didesmethyl and 27,39-O-didesmethyl SAR-943; 
      demethylated-hydroxylated metabolites: 39-O-desmethyl, 23- or 24-hydroxy and 
      39-O-desmethyl, hydroxy piperidine SAR-943 and dihydroxylated metabolites: 
      12-,23- or 24-dihydroxy SAR-943. In addition, several other 
      demethylated-hydroxylated and dihydroxylated metabolites were detected. However, 
      their exact structures could not be identified.
CI  - Copyright (c) 2011 John Wiley & Sons, Ltd.
FAU - Strom, Tobin
AU  - Strom T
AD  - iC42 Clinical Research & Development, Department of Anesthesiology, University of 
      Colorado Denver, Aurora, Colorado 80045-7503, USA.
FAU - Shokati, Touraj
AU  - Shokati T
FAU - Klawitter, Jost
AU  - Klawitter J
FAU - Klawitter, Jelena
AU  - Klawitter J
FAU - Hoffman, Keith
AU  - Hoffman K
FAU - Schiebel, Hans-Martin
AU  - Schiebel HM
FAU - Christians, Uwe
AU  - Christians U
LA  - eng
GR  - P30 DK04852/DK/NIDDK NIH HHS/United States
GR  - R01 DK065094/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Mass Spectrom
JT  - Journal of mass spectrometry : JMS
JID - 9504818
RN  - IGL4DTS8F8 (SAR943)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Drug Stability
MH  - Drug-Eluting Stents
MH  - Humans
MH  - Hydroxylation
MH  - Mass Spectrometry/*methods
MH  - Methylation
MH  - Microsomes, Liver/chemistry/*metabolism
MH  - Sirolimus/*analogs & derivatives/analysis/chemistry/metabolism
EDAT- 2011/06/15 06:00
MHDA- 2011/09/08 06:00
CRDT- 2011/06/15 06:00
PHST- 2011/06/15 06:00 [entrez]
PHST- 2011/06/15 06:00 [pubmed]
PHST- 2011/09/08 06:00 [medline]
AID - 10.1002/jms.1930 [doi]
PST - ppublish
SO  - J Mass Spectrom. 2011 Jul;46(7):615-24. doi: 10.1002/jms.1930.