Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy.
Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. erin.milner@amedd.army.mil
Erin
E
Milner
Jason
J
Sousa
Brandon
B
Pybus
Jennifer
J
Auschwitz
Diana
D
Caridha
Sean
S
Gardner
Kristina
K
Grauer
Erin
E
Harris
Mark
M
Hickman
Michael P
MP
Kozar
Patricia
P
Lee
Susan
S
Leed
Qigui
Q
Li
Victor
V
Melendez
Jay
J
Moon
Franklyn
F
Ngundam
Michael
M
O'Neil
Sandi
S
Parriott
Brittney
B
Potter
Rick
R
Sciotti
Anchalee
A
Tangteung
Geoffrey S
GS
Dow
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007665:Ketotifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects / Q000302:isolation & purification; D010963:Plasmodium falciparum / Q000187:drug effects / Q000302:isolation & purification; D011355:Prodrugs
D000962:Antimalarials; D011355:Prodrugs; C578473:norketotifen; D007665:Ketotifen