Structure elucidation of aplidine metabolites formed in vitro by human liver microsomes using triple quadrupole mass spectrometry.
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.
Brandon
Esther F A
EF
Utrecht University, Faculty of Pharmaceutical Sciences, Department of Biomedical Analysis, Division of Drug Toxicology, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
van Ooijen
Ronald D
RD
Sparidans
Rolf W
RW
Lázaro
Luis López
LL
Heck
Albert J R
AJ
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D047630:Depsipeptides / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008832:Microchemistry / Q000379:methods; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D036103:Nanotechnology; D010456:Peptides, Cyclic; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C098980:plitidepsin