title: In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.
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 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.
authors.affiliation: INSERM U547, Institut Pasteur, 1 rue du Professeur P. Calmette, B.P. 245, 59019 Lille Cedex, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Daher
authors.forename: Lydie
authors.initials: L
authors.lastname: Pelinski
authors.forename: Sylvie
authors.initials: S
authors.lastname: Klieber
authors.forename: Freddy
authors.initials: F
authors.lastname: Sadoun
authors.forename: Viviane
authors.initials: V
authors.lastname: Meunier
authors.forename: Martine
authors.initials: M
authors.lastname: Bourrié
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
authors.forename: François
authors.initials: F
authors.lastname: Guillou
authors.forename: Gérard
authors.initials: G
authors.lastname: Fabre
authors.forename: Jacques
authors.initials: J
authors.lastname: Brocard
authors.forename: Laurent
authors.initials: L
authors.lastname: Fraisse
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Maffrand
authors.forename: Jamal
authors.initials: J
authors.lastname: Khalife
authors.forename: Daniel
authors.initials: D
authors.lastname: Dive
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005296:Ferrous Compounds / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D000075163:Metallocenes; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D007527:Isoenzymes; D000075163:Metallocenes; D011994:Recombinant Proteins; C479230:ferroquine; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A