title: The toxicity of amodiaquine and its principal metabolites towards mononuclear leucocytes and granulocyte/monocyte colony forming units.
abstract: The cytotoxicity of amodiaquine (AQ), amodiaquine quinoneimine (AQQI) and desethylamodiaquine (AQm) has been assessed in comparison with that of chloroquine (CQ) using mononuclear leucocytes (MNL) and granulocyte/monocyte colony forming units (GM-CFU) from haematologically normal subjects. Toxicity toward MNL was assessed after 2 h and 16 h incubations with each compound. After 2 h, AQ, AQm and AQQI but not CQ (within the concentration range 1-100 mumols l-1) produced a significant decrease in cell viability. After 16 h, all four compounds significantly increased cell death. After both 2 h and 16 h incubations CQ was the least toxic and AQQI the most toxic of the four compounds towards MNL. Toxicity to GM-CFU was assessed by the inhibition of colony formation in vitro. After 10-14 days incubation, there was significant concentration-dependent inhibition of colony formation by AQ, AQm, AQQI and CQ (within the range 0.1-10.0 mumols l-1). There were no significant differences between the ability of the four compounds to inhibit colony formation but toxicity towards GM-CFU was observed at drug concentrations at least 10-fold lower than those that were toxic to MNL. These data show that the four compounds are equally toxic in vitro toward GM-CFU, although some differences in their toxicity toward MNL were seen. The possible mechanisms of AQ's toxicity are discussed.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool.
authors.forename: P A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: J W
authors.initials: JW
authors.lastname: Coleman
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: A M
authors.initials: AM
authors.lastname: Breckenridge
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000633:toxicity; D003114:Colony-Forming Units Assay; D006098:Granulocytes / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects*
chemical_list: D000655:Amodiaquine; C047386:desethylamodiaquine; D002738:Chloroquine