A comparative study of the iron-clearing properties of desferrithiocin analogues with desferrioxamine B in a Cebus monkey model.
A comparative study of the iron-clearing properties of subcutaneously administered desferrioxamine B (DFO) with those of orally administered desferrithiocin sodium salt (1), desmethyl desferrithiocin (2), desazadesmethyl desferrithiocin sodium salt (3), desazadesmethyl desferrithiocin pivaloyloxymethyl ester (4), and desazadesmethyl-5,5-dimethyl desferrithiocin (5) in an iron-loaded Cebus monkey model and a non-iron overloaded bile duct-cannulated rat model is presented. All six drugs, which performed well in rodent studies, demonstrated increased efficiency in the Cebus monkey model. When administered to rodents at a daily dosage of 384 mumol/kg over a period of 10 days, drug 1 demonstrated severe renal toxicity. whereas drugs 3, 4, and 5 exhibited severe gastrointestinal (GI) toxicity. Under the same experimental protocol, drug 2 did not show significant toxic side effects. In addition, to further evaluate the iron-clearing properties of analogue 2, a dose-response study was performed in the primates that showed that iron excretion increased in a dose-dependent fashion.
Bergeron
R J
RJ
Department of Medicinal Chemistry, Medicine, University of Florida, Gainesville 32610-0485.
Streiff
R R
RR
Creary
E A
EA
Daniels
R D
RD
King
W
W
Luchetta
G
G
Wiegand
J
J
Moerker
T
T
Peter
H H
HH
D000818:Animals; D002428:Cebus; D003676:Deferoxamine / Q000008:administration & dosage / Q000378:metabolism*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D005243:Feces / Q000737:chemistry; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D007501:Iron / Q000378:metabolism* / Q000652:urine; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity
D004095:Dihydropyridines; D017262:Siderophores; D013844:Thiazoles; D007501:Iron; D003676:Deferoxamine; C050223:desferrithiocin