In vitro metabolism of a triclyclic alkaloid (M445526) in human liver microsomes and hepatocytes.
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.
McCormick
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AD
Drug Metabolism and Pharmacokinetics Department, AstraZeneca, Alderley Park, Macclesfield, UK. alex.mccormick@astrazeneca.com
Slamon
D L
DL
Lenz
E M
EM
Phillips
P J
PJ
King
C D
CD
McKillop
D
D
Roberts
D W
DW
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
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D050257:Tubulin Modulators; D003078:Colchicine