In vitro metabolism of a triclyclic alkaloid (M445526) in human liver microsomes and hepatocytes

• Published in: Xenobiotica Vol. 37; no. 9; pp. 972 - 985
• Main Authors: McCormick, A. D., Slamon, D. L., Lenz, E. M., Phillips, P. J., King, C. D., Mckillop, D., Roberts, D. W.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.09.2007; Taylor & Francis
• Subjects: Adult; Aged; Alkaloids - chemistry; Alkaloids - pharmacokinetics; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacokinetics; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Chromatography, High Pressure Liquid; Colchicine - analogs & derivatives; Colchicine - chemistry; Colchicine - pharmacokinetics; Female; Hepatocytes - metabolism; human hepatocyte metabolism; human microsomal metabolism; Humans; In Vitro Techniques; Male; Mass Spectrometry; Microsomes, Liver - metabolism; Middle Aged; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacokinetics; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacokinetics; vascular targeting agent; ZD6126
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498250701620718

The in vitro metabolism of M445526 (ZD6126 phenol) was investigated by incubating [14C]-M445526 at a concentration of 10 µg ml−1 with human hepatic microsomes (4 mg ml−1) or human hepatocytes (2 × 106 cells ml−1) for up to 180 min. Following incubation with microsomes and hepatocytes, up to 78% and 40% of [14C]-M445526 was metabolized after 180 and 120 min, respectively. High-performance liquid chromatography (HPLC) with radiochemical detection confirmed extensive metabolism of [14C]-M445526 by microsomes and hepatocytes. Mass spectrometry and 1H-NMR spectroscopy enabled structural identification of up to eight metabolites. Human liver microsomes formed one major (O-desmethyl) and three minor (a further O-desmethyl and two different hydroxylated) phase I metabolites. Human hepatocytes produced one major metabolite, a sulphate conjugate of the major O-desmethyl metabolite formed by microsomes. Four minor metabolites were also formed, primarily by O-demethylation with subsequent glucuronidation. Taken collectively, [14C]-M445526 underwent extensive in vitro metabolism by human liver fractions. These data were confirmed by subsequent human in vivo studies.