In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: A comparison with human liver microsomes

Luigi Quintieri, Marianna Fantin, Pietro Palatini, Sara De Martin, Antonio Rosato, Michele Caruso, Cristina Geroni, Maura Floreani

Research output: Contribution to journalArticlepeer-review

Abstract

We recently demonstrated that nemorubicin (MMDX), an investigational antitumor drug, is converted to an active metabolite, PNU-159682, by human liver cytochrome P450 (CYP) 3A4. The objectives of this study were: (1) to investigate MMDX metabolism by liver microsomes from laboratory animals (mice, rats, and dogs of both sexes) to ascertain whether PNU-159682 is also produced in these species, and to identify the CYP form(s) responsible for its formation; (2) to compare the animal metabolism of MMDX with that by human liver microsomes (HLMs), in order to determine which animal species is closest to human beings; (3) to explore whether differences in PNU-159682 formation are responsible for previously reported species- and sex-related differences in MMDX host toxicity. The animal metabolism of MMDX proved to be qualitatively similar to that observed with HLMs since, in all tested species, MMDX was mainly converted to PNU-159682 by a single CYP3A form. However, there were marked quantitative inter- and intra-species differences in kinetic parameters. The mouse and the male rat exhibited Vmax and intrinsic metabolic clearance (CLint) values closest to those of human beings, suggesting that these species are the most suitable animal models to investigate MMDX biotransformation. A close inverse correlation was found between MMDX CLint and previously reported values of MMDX LD50 for animals of the species, sex and strain tested here, indicating that differences in the in vivo toxicity of MMDX are most probably due to sex- and species-related differences in the extent of PNU-159682 formation.

Original languageEnglish
Pages (from-to)784-795
Number of pages12
JournalBiochemical Pharmacology
Volume76
Issue number6
DOIs
Publication statusPublished - Sep 15 2008

Keywords

  • CYP3A enzymes
  • Liver microsomes
  • Nemorubicin oxidative metabolism
  • PNU-159682
  • Sex-and species-related differences

ASJC Scopus subject areas

  • Pharmacology

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