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.
Footnotes
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Part of this work has been presented at the 53rd meeting of the American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics, San Antonio, TX, June 5–9, 2005.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.020651.
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ABBREVIATIONS: LC/MS, liquid chromatography/mass spectrometry; LC/MS/MS, liquid chromatography/tandem mass spectrometry; FKBP-12, FK506 binding protein; MLR, mixed lymphocyte reaction; AUC, area under the curve.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material. -
↵1 Current affiliation: Theragenomics Associates, Grellingen, Switzerland.
- Received January 28, 2008.
- Accepted April 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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