Metabolic map and bioactivation of the anti-tumour drug noscapine

Br J Pharmacol. 2012 Nov;167(6):1271-86. doi: 10.1111/j.1476-5381.2012.02067.x.


Background and purpose: Noscapine is a promising anti-tumour agent. The purpose of the present study was to describe the metabolic map and investigate the bioactivation of noscapine.

Experimental approach: Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics was used to analyse the in vitro incubation mixtures, urine and faeces samples from mice treated with noscapine. Recombinant drug-metabolizing enzymes were employed to identify those involved in noscapine metabolism. Hepatic GSH levels and serum biochemistry were also carried out to determine reactive metabolites of noscapine.

Key results: Several novel phase I metabolites of noscapine were detected after oral gavage of mice, including an N-demethylated metabolite, two hydroxylated metabolites, one metabolite undergoing both demethylation and cleavage of the methylenedioxy group and a bis-demethylated metabolite. Additionally, several novel glucuronides were detected, and their structures were elucidated through MS/MS fragmentology. Recombinant enzymes screening showed the involvement of several cytochromes P450, flavin-containing mono-oxygenase 1 and the UDP-glucuronosyltransferases UGT1A1, UGT1A3, UGT1A9 and UGT2B7, in noscapine metabolism. In vitro glutathione trapping revealed the existence of an ortho-quinone reactive intermediate formed through further oxidation of a catechol metabolite. However, this bioactivation process of noscapine does not occur in vivo. Similar to this result, altered glutathione levels in liver and serum biochemistry revealed no evidence of hepatic damage, thus indicating that, at least in mice, noscapine does not induce hepatotoxicity through bioactivation.

Conclusions and implications: A comprehensive metabolic map and bioactivation evaluation provides important information for the development of noscapine as an anti-tumour drug.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / urine
  • Biotransformation
  • Cytochrome P-450 Enzyme System / metabolism
  • Glucuronosyltransferase / metabolism
  • Glutathione / metabolism
  • Humans
  • Liver / metabolism
  • Male
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Noscapine / pharmacokinetics*
  • Noscapine / urine


  • Antineoplastic Agents
  • Noscapine
  • Cytochrome P-450 Enzyme System
  • Glucuronosyltransferase
  • Glutathione