title: The macrolide everolimus forms an unusual metabolite in animals and humans: identification of a phosphocholine ester.
abstract: The immunosuppressant macrolide everolimus was found to be metabolized in animals and humans to a phosphocholine ester (ATG181), a hitherto unknown type of conjugate in xenobiotic metabolism. The structure of ATG181 was elucidated by mass spectrometry and confirmed by synthesis. ATG181 was among the most prominent metabolites of everolimus in rat, monkey, and human blood and was found also in various tissues of the rat, whereas no ATG181 was identified in the urine and feces of the species investigated. The metabolite showed binding to FK506 binding protein with a 2- to 3-fold higher affinity than everolimus. However, ATG181 exhibited only marginal in vitro immunosuppressive activity and is therefore very unlikely to contribute in a relevant manner to the immunosuppressive effect of everolimus.
authors.affiliation: Novartis Pharma AG, WKL-135.2.21 P.O. Box, CH-4002 Basel, Switzerland. markus.zollinger@novartis.com
authors.forename: Markus
authors.initials: M
authors.lastname: Zollinger
authors.forename: Claudia
authors.initials: C
authors.lastname: Sayer
authors.forename: Robert
authors.initials: R
authors.lastname: Dannecker
authors.forename: Walter
authors.initials: W
authors.lastname: Schuler
authors.forename: Richard
authors.initials: R
authors.lastname: Sedrani
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D004952:Esters; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D013058:Mass Spectrometry; D010767:Phosphorylcholine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004952:Esters; D007166:Immunosuppressive Agents; D010767:Phosphorylcholine; D000068338:Everolimus; D020123:Sirolimus