Biliary Iron Excretion in Rats following Pyridoxal Isonicotinoyl Hydrazone

Abstract

Biliary excretion of iron after administration of pyridoxal isonicotinoyl hydrazone (PIH), a recently identified effective iron-chelating agent, was investigated in rats. PIH administered both intraperitoneally and orally was shown to increase significantly 59Fe excretion into bile of rats which had previously been injected with 59Fe-transferrin to label hepatic parenchymal cells. 59Fe-PIH appears in bile as early as 15 min after chelator administration and the peak of 59Fe-radioactivity in bile is seen 1--5 h following intraperitoneal PIH injection. PIH, administered intraperitoneally, 125--250 mg/kg, increased 24 h biliary radioiron excretion about 35 times and in addition increased urinary and faecal iron excretion. When PIH was given immediately before 59Fe-transferrin, 24 h cumulative biliary 59Fe excretion was even higher. PIH was also demonstrated to increase biliary excretion of radioiron released from 59Fe-haemoglobin catabolysed in reticuloendothelial cells. The effect of PIH was confirmed by estimation of biliary iron concentration using the method of atomic absorption spectrophotometry. Repeated PIH administration to rats decreased 59Fe radioactivity in liver and kidney and increased urinary and faecal iron excretion.

Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity

“…1) by Ponka and colleagues [6,14,89] and was shown to cross membranes efficiently as a free ligand and as an Fe complex, resulting in Fe chelation efficacy that was at least comparable to DFO [90,91]. However, while its advantages have been shown in a multitude of in vitro and in vivo studies [6,89,90,[92][93][94][95][96][97], PIH lacks patent protection. The resulting lack of commercial interest has stifled its progress to clinical trials [94].…”

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…KALINOWSKI AND RICHARDSON (Cikrt et al, 1980). In addition, a decrease in 59 Fe radioactivity was evident in the liver and kidney of rats following repeated PIH administration (Cikrt et al, 1980).…”

“…In addition, a decrease in 59 Fe radioactivity was evident in the liver and kidney of rats following repeated PIH administration (Cikrt et al, 1980). In addition to rat studies, the effects of PIH treatment have also been examined during a phase I clinical trial in both normal and iron-overloaded patients (Brittenham, 1990).…”

Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells

“…8,9,32 The selectivity of PIH for iron is comparable with that of DFO. Studies in rats 33,34 have shown that PIH is able to remove parenchymal and reticuloendothelial (RE) iron and that practically all chelated iron is excreted through the bile. 34 Its in vivo chelating efficiency in rats was equal to, or slightly better than, DFO, and there was no evidence of toxicity at doses up to 500 mg/kg per day.…”