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 pivaloyloxymet...

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Bibliographic Details
Published in:Blood 1993-04, Vol.81 (8), p.2166-2173
Main Authors: BERGERON, R. J, STREIFF, R. R, CREARY, E. A, DANIELS, R. D, KING, W, LUCHETTA, G, WIEGAND, J, MOERKER, T, PETER, H. H
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cebus
Deferoxamine - administration & dosage
Deferoxamine - metabolism
Dihydropyridines - administration & dosage
Dihydropyridines - metabolism
Dihydropyridines - toxicity
Feces - chemistry
Gastrointestinal Diseases - chemically induced
General and cellular metabolism. Vitamins
Iron - metabolism
Iron - urine
Kidney Diseases - chemically induced
Male
Medical sciences
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Siderophores - metabolism
Thiazoles - administration & dosage
Thiazoles - metabolism
Thiazoles - toxicity
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V81.8.2166.2166