PT - JOURNAL ARTICLE AU - Wassim Daher AU - Lydie Pelinski AU - Sylvie Klieber AU - Freddy Sadoun AU - Viviane Meunier AU - Martine Bourrié AU - Christophe Biot AU - François Guillou AU - Gérard Fabre AU - Jacques Brocard AU - Laurent Fraisse AU - Jean-Pierre Maffrand AU - Jamal Khalife AU - Daniel Dive TI - IN VITRO METABOLISM OF FERROQUINE (SSR97193) IN ANIMAL AND HUMAN HEPATIC MODELS AND ANTIMALARIAL ACTIVITY OF MAJOR METABOLITES ON <em>PLASMODIUM FALCIPARUM</em> AID - 10.1124/dmd.104.003202 DP - 2006 Apr 01 TA - Drug Metabolism and Disposition PG - 667--682 VI - 34 IP - 4 4099 - http://dmd.aspetjournals.org/content/34/4/667.short 4100 - http://dmd.aspetjournals.org/content/34/4/667.full SO - Drug Metab Dispos2006 Apr 01; 34 AB - 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 metabolized 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. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, 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 with 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. The American Society for Pharmacology and Experimental Therapeutics