RT Journal Article
SR Electronic
T1 IN VITRO METABOLISM OF FERROQUINE (SSR97193) IN ANIMAL AND HUMAN HEPATIC MODELS AND ANTIMALARIAL ACTIVITY OF MAJOR METABOLITES ON <em>PLASMODIUM FALCIPARUM</em>
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 667
OP 682
DO 10.1124/dmd.104.003202
VO 34
IS 4
A1 Wassim Daher
A1 Lydie Pelinski
A1 Sylvie Klieber
A1 Freddy Sadoun
A1 Viviane Meunier
A1 Martine Bourrié
A1 Christophe Biot
A1 François Guillou
A1 Gérard Fabre
A1 Jacques Brocard
A1 Laurent Fraisse
A1 Jean-Pierre Maffrand
A1 Jamal Khalife
A1 Daniel Dive
YR 2006
UL http://dmd.aspetjournals.org/content/34/4/667.abstract
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