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

0090-9556/06/3404-667-682$20.00
DMD 34:667-682, 2006

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IN VITRO METABOLISM OF FERROQUINE (SSR97193) IN ANIMAL AND HUMAN HEPATIC MODELS AND ANTIMALARIAL ACTIVITY OF MAJOR METABOLITES ON PLASMODIUM FALCIPARUM

Wassim Daher, Lydie Pelinski, Sylvie Klieber, Freddy Sadoun, Viviane Meunier, Martine Bourrié, Christophe Biot, François Guillou, Gérard Fabre, Jacques Brocard, Laurent Fraisse, Jean-Pierre Maffrand, Jamal Khalife, and Daniel Dive

Institut National de la Sante et de la Recherche Medicale U547, Institut Pasteur, Lille, France (W.D., J.K., D.D.); Unité de Catalyse et de Chimie du Solide, Unité Mixte de Recherche Centre National de la Recherche Scientifique 8181, Ecole Nationale Supérieure de Chimie de Lille, Villeneuve d'Ascq, France (L.P., C.B., J.B.); Sanofi-Aventis Recherche, Discovery Metabolism, Pharmacokinetics and Safety Department, Montpellier, France (F.S., V.M., S.K., M.B., F.G., G.F.); and Sanofi-Aventis Recherche, Toulouse, France (L.F., J.-P.M.)

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.

Address correspondence to: Daniel Dive, INSERM U547, Institut Pasteur, 1 rue du Professeur P. Calmette, B.P. 245, 59019 Lille Cedex, France. E-mail: daniel.dive{at}pasteur-lille.fr






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