title: In vitro metabolism of a triclyclic alkaloid (M445526) in human liver microsomes and hepatocytes.
abstract: The in vitro metabolism of M445,526 (ZD6,126 phenol) was investigated by incubating [(14)C]-M445,526 at a concentration of 10 microg ml(-1) with human hepatic microsomes (4 mg ml(-1)) or human hepatocytes (2 x 10(6) cells ml(-1)) for up to 180 min. Following incubation with microsomes and hepatocytes, up to 78% and 40% of [(14)C]-M445,526 was metabolized after 180 and 120 min, respectively. High-performance liquid chromatography (HPLC) with radiochemical detection confirmed extensive metabolism of [(14)C]-M445,526 by microsomes and hepatocytes. Mass spectrometry and (1)H-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, [(14)C]-M445,526 underwent extensive in vitro metabolism by human liver fractions. These data were confirmed by subsequent human in vivo studies.
authors: Drug Metabolism and Pharmacokinetics Department, AstraZeneca, Alderley Park, Macclesfield, UK. alex.mccormick@astrazeneca.com
authors: A D
authors: AD
authors: McCormick
authors: D L
authors: DL
authors: Slamon
authors: E M
authors: EM
authors: Lenz
authors: P J
authors: PJ
authors: Phillips
authors: C D
authors: CD
authors: King
authors: D
authors: D
authors: McKillop
authors: D W
authors: DW
authors: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000470:Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics*; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D050257:Tubulin Modulators / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D050257:Tubulin Modulators; D003078:Colchicine