title: Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns.
abstract: 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.
authors.affiliation: iC42 Clinical Research & Development, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado 80045-7503, USA.
authors.forename: Tobin
authors.initials: T
authors.lastname: Strom
authors.forename: Touraj
authors.initials: T
authors.lastname: Shokati
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: Keith
authors.initials: K
authors.lastname: Hoffman
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Schiebel
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
mesh_terms: D004355:Drug Stability; D054855:Drug-Eluting Stents; D006801:Humans; D006900:Hydroxylation; D013058:Mass Spectrometry / Q000379:methods*; D008745:Methylation; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000378:metabolism
chemical_list: C476498:SAR943; D020123:Sirolimus