Metabolism of docetaxel in mice.
Previous studies have shown by quantification of the parent drug and the known metabolites M-1, M-2, M-3 and M-4 that the mass balance of docetaxel in mice and humans is not complete. We therefore used reversed-phase high-performance liquid chromatography (HPLC) with photodiode array (PDA) detection and tandem mass spectrometry to trace and identify putative metabolites in the feces and bile of mice injected intravenously with docetaxel. HPLC-PDA revealed two metabolic products in the feces and more than ten potential new metabolites in the bile. Mass spectrometry was performed on docetaxel reference compound, on the known metabolites M-1, M-2, M-3 and M-4, and on HPLC eluate fractions containing metabolic products, six fractions originating from the bile and two from the feces. The mass spectra of the most abundant unknown metabolite in the bile and the feces were identical, and indicated that this structure contained a carboxyl moiety at the tert-butyl group. Under the conditions of storage this product degraded to metabolite M-4. All other unknown metabolites found in the bile samples were oxidized products, with the oxidations in both the C-13 side chain and the baccatin structure, the latter being a new finding.
Bardelmeijer
Heleen A
HA
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. o.v.tellingen@nki.nl
Roelofs
Arjan B G H
AB
Hillebrand
Michel J X
MJ
Beijnen
Jos H
JH
Schellens
Jan H M
JH
van Tellingen
Olaf
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000077143:Docetaxel; D005243:Feces / Q000737:chemistry; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D021241:Spectrometry, Mass, Electrospray Ionization; D043823:Taxoids / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel