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Xenobiotica
the fate of foreign compounds in biological systems
Volume 37, 2007 - Issue 9
65
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Research Article

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

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Pages 972-985 | Received 06 Jun 2007, Accepted 09 Aug 2007, Published online: 22 Sep 2008
 

Abstract

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.

Acknowledgement

The authors would like to acknowledge Jenny Stewart of InforMed Direct for support in the preparation of this paper.

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