Biliary iron excretion in rats following treatment with analogs of pyridoxal isonicotinoyl hydrazone
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
9596686
PII: S0006-4971(20)55488-8
Knihovny.cz E-zdroje
- MeSH
- chelátory železa chemie farmakologie MeSH
- isoniazid analogy a deriváty chemie farmakologie MeSH
- krysa rodu Rattus MeSH
- potkani Wistar MeSH
- pyridoxal analogy a deriváty chemie farmakologie MeSH
- železo metabolismus MeSH
- žluč metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chelátory železa MeSH
- isoniazid MeSH
- pyridoxal isonicotinoyl hydrazone MeSH Prohlížeč
- pyridoxal MeSH
- železo MeSH
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 approximately 0.8 microg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 microg 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 microg 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.