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Drug Metabolism and Disposition Fast Forward
First published on April 30, 2008; DOI: 10.1124/dmd.108.020651
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Received for publication January 28, 2008.
Revised April 21, 2008.
Accepted for publication April 24, 2008.

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

Markus Zollinger 1*, Claudia Sayer 1, Robert Dannecker 1, Walter Schuler 2, Richard Sedrani 2

1 Novartis Pharma AG, Basel, Switzerland 2 Novartis Institutes for BioMedical Research, Basel, Switzerland

* Address correspondence to: E-mail: markus.zollinger{at}novartis.com

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 while no ATG181 was identified in the urine and feces of the species investigated. The metabolite showed binding to FK506 binding protein with a two- to three-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.


Key words: analytical chemistry, anticancer agents, immunosuppression, mass spectrometry, metabolite identification, phase II drug metabolism, structure elucidation




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