Biliary Iron Excretion in Rats Following Treatment With Analogs of
Pyridoxal Isonicotinoyl Hydrazone
Karel Bláha,
Miroslav Cikrt,
Jana Nerudová, and
Helena
Forn
sková, and P
emysl Po
ka
From the Centre of Industrial Hygiene and Occupational Diseases,
National Institute of Public Health, Prague, Czech Republic; and the
Lady Davis Institute for Medical Research of the Jewish General
Hospital and Departments of Physiology and Medicine, McGill University,
Montreal, Quebec, Canada.
Iron overload is a major life-threatening complication of
thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective
iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise
for the treatment of iron overload. More recently, over 40 analogs of
PIH were synthesized, and some of them proved to be very potent in
mobilizing 59Fe in vitro from 59Fe-labeled
cells. In this study, we show that PIH analogs such as pyridoxal
benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH),
pyridoxal m-fluorobenzoyl hydrazone (PFBH), and
pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to
mobilize iron from cells in vitro, are also effective in vivo. All of
these chelators significantly enhanced biliary excretion of iron
(measured by atomic absorption spectrophotometry) following their
intraperitoneal (IP) and/or oral administration to rats. The
most effective was PFBH, which increased iron concentration in the bile
about 150-fold, as compared with basal biliary iron concentration,
within 1 hour following a single IP dose of 0.2 mmol/kg body
weight. In contrast, desferrioxamine increased the biliary
iron concentration only 20-fold to 30-fold under the same conditions.
Moreover, while control rats excreted 
0.8 µg Fe in 2 hours,
treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative
excretions of 87, 59, and 22 µg Fe, respectively, in the same period
of time. Interestingly, PMBH was also quite effective following gastric
administration, resulting in a 6-hour cumulative value of 34 µg Fe.
These compounds are nontoxic and are inexpensive and easy to make.
Their further evaluation as candidate drugs for the treatment of iron
overload is warranted.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4368-4372
© 1998 by The American Society of Hematology.
