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Drug Metabolism and Disposition Fast Forward
First published on April 30, 2008; DOI: 10.1124/dmd.108.020651

0090-9556/08/3608-1457-1460$20.00
DMD 36:1457-1460, 2008

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SHORT COMMUNICATION

The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine EsterFormula

Markus Zollinger, Claudia Sayer, Robert Dannecker1, Walter Schuler, and Richard Sedrani

Novartis Pharma AG, Basel, Switzerland (M.Z., C.S., R.D.); and Novartis Institutes for BioMedical Research, Basel, Switzerland (W.S., R.S.)

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.

Address correspondence to: Markus Zollinger, Novartis Pharma AG, WKL-135.2.21 P.O. Box, CH-4002 Basel, Switzerland. E-mail: markus.zollinger{at}novartis.com






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