RT Journal Article
SR Electronic
T1 The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1457
OP 1460
DO 10.1124/dmd.108.020651
VO 36
IS 8
A1 Markus Zollinger
A1 Claudia Sayer
A1 Robert Dannecker
A1 Walter Schuler
A1 Richard Sedrani
YR 2008
UL http://dmd.aspetjournals.org/content/36/8/1457.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics