Iron dissociates from the NaFeEDTA complex prior to or during intestinal absorption in rats.

Sodium iron ethylenediaminetetraacetate (NaFeEDTA) has superior iron bioavailability especially in foods containing iron absorption inhibitors. However, mechanisms involved in the absorption and subsequent partitioning of iron complexed with EDTA are poorly understood. Our objectives were to compare retention and tissue distribution of iron administered to rats either as FeSO4 or NaFeEDTA, either orally (OR) or subcutaneously (SC). Weanling rats were fed semipurified diets supplemented with either FeSO4 or NaFeEDTA for 7 days. They were then given a meal containing 59Fe-labeled FeSO4 or NaFeEDTA, or they were injected SC with these two forms of radiolabeled Fe. 59Fe retention was measured by whole body counting. Urine was collected and counted at 24 h intervals throughout the counting period. Tissue samples were analyzed for nonheme iron and 59Fe activity. Absorption of iron from FeSO4 or NaFeEDTA was similar (57.7 and 53.4%, respectively). Seventy-seven percent of the injected Na59FeEDTA was excreted in the urine within 24 h, whereas only 0.5, 0.8, and 1.4% of the injected 59FeSO4, oral 59FeSO4, and oral Na59FeEDTA, respectively, was excreted in the urine. The nonheme iron content was lower in the liver and spleen, by 56.8 and 28.4%, respectively, among rats consuming the NaFeEDTA diet as compared to rats fed FeSO4. We conclude that iron is dissociated from EDTA prior to or during intestinal absorption and that some fraction of the dissociated EDTA is absorbed separately from the iron.

ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture.

ICL670A (formerly CGP 72 670) or 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]- benzoic acid is a tridentate iron-selective synthetic chelator of the bis-hydroxyphenyl-triazole class of compounds. The present studies used selective radioiron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to define the source of iron chelated in vivo by ICL670A and its mode of excretion, to examine its ability to remove iron directly from iron-loaded myocardial cells, and to examine its ability to interact with other chelators through a possible additive or synergistic effect. Results indicate that ICL670A given orally is 4 to 5 times more effective than parenteral deferoxamine (DFO) in promoting the excretion of chelatable iron from hepatocellular iron stores. The pattern of iron excretion produced by ICL670A is quite different from that of DFO and all iron excretion is restricted to the bile regardless of whether it is derived from RE or hepatocellular iron stores. Studies in heart cell cultures have shown a favorable interaction between DFO and ICL670A manifested in improved chelating efficiency of ICL670A, which is most probably explained by an exchange of chelated iron between ICL670A and DFO. These unique chelating properties of ICL670A may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice.

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).

Metabolism of 51Cr, 54Mn, 59Fe and 60Co in lactating dairy cows.

Different radionuclides which can be released by nuclear installations (Na2(51) CrO4 , 54MnCl2 , 59FeCl3 and 60CoCl2 ) were given to lactating dairy cows either orally or by intravenous (i.v.) injection. Excretion into feces and urine as well as secretion into milk were followed for several weeks. Distribution of activity in organs was determined at sacrifice 102 days after oral and 70 days after i.v. administration. After ingestion, excretion of chromate followed a three-term exponential function with half-lives of 0.88, 3.7 and 26 days. Intestinal absorption was on the order of 0.1-0.2%. About 63% of injected chromate was excreted into urine, about 18% into feces and about 3.6% into milk. Orally administered chromate was concentrated in liver, intestine and spleen. The transfer coefficient into milk was about 1 X 10(-5) days/1. Less than 1% of an ingested dose of manganese was absorbed. Excretion occurred mainly into feces and followed a three-term exponential function. Very little manganese was excreted into urine or secreted into milk. Manganese is concentrated in brain, pancreas, kidney and heart but the differences in concentration are small. The body burden is, therefore, mainly determined by manganese in muscle, skin and bone. The transfer coefficient of manganese into milk is about 3 X 10(-5). Excretion of iron into feces after oral administration follows a three-term exponential function with a small component having a half-life of 72 days. Intestinal absorption is on the order of 0.5-2% of the dose. After i.v. administration, 7% of the dose is excreted in the feces displaying two components of turnover. Very little iron is excreted into urine. Secretion into milk also follows a two-term exponential function. The transfer coefficient of iron into milk is about 3 X 10(-5). About 0.6% of an oral and about 94% of an i.v. dose were recovered from the cows at sacrifice. Most activity was present in blood, liver and spleen. Excretion of radiocobalt into feces after oral administration is described by a three-term exponential function, while excretion into milk and urine is described by two-term exponential functions. Long-lived components in urine and milk represent about 5-10% of the activity absorbed. Only 1-2% of an oral cobalt dose is absorbed and 0.05% of an oral and 5.85% of an i.v. dose is recovered from the cow at sacrifice where concentrations are highest in kidney and thyroid. The body burden depends mainly on cobalt in muscle, skin and bone. The transfer coefficient of cobalt into milk is about 7.5 X 10(-5).