Structure elucidation of aplidine metabolites formed in vitro by human liver microsomes using triple quadrupole mass spectrometry

✍ Scribed by Esther F. A. Brandon; Ronald D. van Ooijen; Rolf W. Sparidans; Luis López Lázaro; Albert J. R. Heck; Jos H. Beijnen; Jan H. M. Schellens

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 467 KB
• Volume: 40
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/jms.863

✦ Synopsis

Abstract

The cyclic depsipeptide aplidine is a new anti‐cancer drug of marine origin. Four metabolites of this compound were found after incubation with pooled human microsomes using gradient high‐performance liquid chromatography with ultraviolet detection. After chromatographic isolation, the metabolites have been identified using nano‐electrospray triple quadrupole mass spectrometry. A highly specific sodium‐ion interaction with the cyclic structure opens the depsipeptide ring, and cleavage of the amino acid residues gives sequence information when activated by collision‐induced dissociation in the second quadrupole. The aplidine molecule could undergo the following metabolic reactions: hydroxylation at the isopropyl group (metabolites apli‐h 1 and apli‐h 2); C‐dealkylation at the N(Me)‐leucine group (metabolite apli‐da); hydroxylation at the isopropyl group and C‐dealkylation at the N(Me)‐leucine group (metabolite apli‐da/h), and C‐demethylation at the threonine group (metabolite apli‐dm). The identification of these metabolites formed in vitro may greatly aid the elucidation of the metabolic pathways of aplidine in humans. Copyright © 2005 John Wiley & Sons, Ltd.