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Drug Metabolism and Disposition Fast Forward
First published on January 13, 2006; DOI: 10.1124/dmd.104.003202

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Received for publication December 10, 2004.
Revised December 15, 2005.
Accepted for publication January 12, 2006.

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum

Wassim E Daher 1, Lydie Pelinski 2, Sylvie Klieber 3, Freddy Sadoun 3, Viviane Meunier 3, Martine Bourrie 3, Christophe Biot 2, Francois Guillou 3, Gerard Fabre 3, Jacques Brocard 2, Laurent Fraisse 4, Jean Pierre Maffrand 5, Jamal Khalife 1, Daniel Dive 1*

1 Inserm, U547 2 Ecole Normale Superieure de Chimie de Lille, CNRS UMR 8010 3 Sanofi Aventis Research, Discovery Metabolism 4 Sanofi Aventis Research, Discovery Department 5 Sanofi Aventis Research, Discovery Department

* Address correspondence to: E-mail: daniel.dive{at}pasteur-lille.fr

Abstract

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolised mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine, and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. CYP isoforms 2C9, 2C19, 3A4 and also possibly, in some patients, isoform 2D6 are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine sensitive) and W2 (chloroquine resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared to that of ferroquine, however the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.


Key words: analytical chemistry, drug analysis, drug development, drug efficacy, hepatocytes, HPLC, human CYP enzymes, in vitro toxicity assays, mass spectrometry, metabolite identification




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