Comparison of the effectiveness of several chelators after single administration on the toxicity,excretion, and distribution of cadmium

The effect of several chelating agents (diethyldithiocarbamic acid, DDC; nitrilotriacetic acid, NTA; 2,3-dimercaptopropanol, BAL; dl-penicillamine, PEN; 2,3-dimercaptosuccinic acid, DMSA; ethylenediaminetetraacetic acid, EDTA; and diethylenetriaminepentaacetic acid, DTPA) on the toxicity, excretion, and distribution of Cd was determined in male Swiss Webster mice weighing 30–45 g. Chelators were administered intraperitoneally at a dose equal to one-fourth of their respective LD50. To determine the effect of the various chelators on the toxicity of Cd, various doses of CdCl₂ (4–10 mg Cd/kg, iv) were given, followed immediately by one of the chelators. Survival was recorded at the end of 14 days. Significant increases in survival were noted with DMSA, EDTA, and DTPA, with DTPA being the most effective. Radiolabeled Cd (¹⁰⁹CdCl₂, 1 mg Cd/kg, iv) was used in a 24-hr excretion and distribution study. The chelators were given immediately after the Cd. DTPA, followed by EDTA and then DMSA, was consistently the most effective in increasing the urinary excretion of Cd and reducing the concentration of Cd found in various tissues. NTA, BAL, DDC, and PEN had no orerall beneficial effects. DTPA appears to be the most effective agent of those tested in the prevention of acute Cd intoxication.     

Comparison of the antidotal efficacy of polyamincarboxylic acids (CDTA and DTPA) with time after acute zinc poisoning

The effect of increasing the time interval between acute zinc exposure and chelation therapy was studied in male Swiss mice. Cyclohexanediaminetetraacetic acid (CDTA), and diethylenetriaminepentaacetic acid (DTPA) were administered ip at 0, 0.25, 0.5, 2, 12, or 24 hr after ip administration of 0.40 mmol/kg of zinc acetate dihydrate. Chelating agents were given at doses equal to 1/3 of their respective LD50 values. Effectiveness of chelation therapy was determined by measuring the ability of the chelators to increase the elimination of zinc and decrease the concentration of the metal in various tissues. Treatment with DTPA or CDTA increased significantly the urinary and fecal excretion of zinc when the chelators were administered at various times following zinc exposure. The greatest antidotal efficacy of the chelating agents was observed at 0.50 hr after zinc injection. Nevertheless, the effectiveness of DTPA and CDTA was decreasing when the chelators were administered later. DTPA was more effective than CDTA in the prevention of acute zinc intoxication. CDTA would be considered as a possible alternative.     

The effect of repeated administration of several chelators on the distribution and excretion of cadmium

The effect of repeated administration of several chelators on the distribution and excretion of cadmium (Cd) was determined in male Swiss Webster mice. Radioisotopic Cd (¹⁰⁹Cd, 1 mg Cd/kg) was administered iv; 48 hr later (after maximal induction of hepatic metallothionein) daily chelation therapy was initiated. Mice received one of the following ip treatments for 5 days: saline, diethyldithiocarbamic acid (DDC), nitrilotriacetic acid (NTA), 2,3-dimercaptopropanol (BAL), d,l-penicillamine (PEN), 2,3-dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA), or diethylenetriaminepentaacetic acid (DTPA). Mice were housed in metabolic cages, and urine and feces were collected daily for 7 days. After 5 days of chelation therapy (7 days after Cd), the mice were killed and various organs removed. DTPA, EDTA, DMSA, and BAL significantly increased the excretion of Cd into urine. DDC significantly increased the fecal elimination of Cd and altered tissue concentrations of Cd. The concentration of Cd in DDC-treated mice was increased in testes, muscle, and brain and decreased in kidney, spleen, and blood. The observed increase in urinary excretion of Cd when certain chelators were administered after the induction of hepatic metallothionein suggests that increasing the duration of chelation therapy may decrease the concentrations of Cd in tissues and hence, reduce the toxicity of the metal.     

The effect of chelating agents on the excretion of endogenous metals

The effect of various chelating agents on the urinary elimination of several endogenous metals was determined in male Swiss Webster mice. The chelating agents diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 2,3-dimercaptosuccinic acid (DMSA), penicillamine (PEN), sodium diethyldithiocarbamate (DDC), nitrilotriacetic acid (NTA), and 2,3-dimercaptopropanol (BAL) were administered once daily for 3 consecutive days or twice daily for 7 consecutive days at a dose equivalent to one-fourth of their respective LD50 values. Neither treatment protocol produced significant pathological lesions visible by light microscopic examination of heart, liver, skeletal muscle, small intestine, and kidney. However, marked weight losses were observed in mice given EDTA or DTPA twice daily for 7 days. The concentrations of Zn, Cu, Mg, Mn, Fe, and Ca were determined in daily urine from mice given chelators once daily for 3 consecutive days. DTPA significantly increased the urinary elimination of Cu, Fe, Zn, and Mn. The urinary excretion of Fe, Zn, and Mn was increased by EDTA. Treatment with DMSA or BAL increased the urinary elimination of Fe. Administration of NTA had no effect on the urinary elimination of any of the metals studied. None of the chelators significantly affected the excretion of Mg or Ca. Thus, certain chelating agents were shown to produce marked effects on the excretion of endogenous metals which suggests that chronic therapy with these agents may be accompanied by possible depletion of essential metals.     

The removal of zinc from the mouse by polyamincarboxylic acids (CDTA and DTPA) following semichronic zinc ingestion

Effects of ip treatment with diethylenetriaminepentaacetic acid (DTPA), and cyclohexanediaminetetraacetic acid (CDTA) on the zinc (Zn) excretion and Zn levels in selected mouse organs and tissues were assessed after mice were offered deionized water containing zinc acetate dihydrate (108 mg/kg/day) as the sole drinking fluid for 4 weeks. Following this period, the Zn-containing water was replaced by tap water and therapy with DTPA or CDTA was initiated. The animals received 6 injections of chelators or 0.9% saline (control group) on alternate days for 2 weeks of treatment. The dose of chelating agents was approximately equal to 1/4 of their respective ip LD50 values. Mice were housed in metabolic cages, and urine and feces were collected 24 hr after the first, fourth and sixth administration of the chelators. Six animals in each group were sacrificed at the same days. Although feces was the predominant route of elimination for Zn, only DTPA significantly increased the fecal excretion of Zn after the first administration of chelator. Treatment with DTPA or CDTA resulted in a significant decrease in the concentration of Zn in brain, spleen, and heart after the first injection. DTPA was consistently the most effective in increasing the urinary and fecal excretion of Zn and reducing the concentration of the metal found in various tissues. CDTA would be considered as a possible alternative.     

Oral cadmium chloride intoxication in mice: effects of chelation

In acute oral cadmium intoxication, the immediate target organ is the gastrointestinal tract. In this study, toxic effects following oral administration of CdCl2 to mice by stomach tube included intestinal paralysis, constipation and necrosis of the gastrointestinal epithelia. Tissue damage in liver, kidneys and testes developed in survivors due to the systemic toxicity of absorbed cadmium. Chelation of the Cd2+ ion by STPP, EDTA or DTPA prior to oral administration reduced mortality, tissue damage and whole body retention of cadmium. Other chelators (cysteine, NTA, DDC) only marginally affected the whole-body retention. DDC even enhanced the inhibition of intestinal motility caused by cadmium. DTPA and DDC decreased the relative deposition in the liver and increased the relative renal deposition. DDC also increased the relative cadmium deposition in brain, lung, spleen and testes. Among the chelators tested, DTPA was most efficient in preventing toxic effects of oral cadmium.     

Assessment of potential aluminum chelators in an octanol/aqueous system and in the aluminum-loaded rabbit

Aluminum (Al) solubilization from Al borate and its distribution in an octanol/aqueous system (Do/w) were determined in the absence and presence of 12 potential Al chelators. Citrate, N,N'-bis-(2-hydroxybenzyl)ethylenediamine- N,N'-diacetic acid (HBED), cyclohexane-1,2-diaminotetraacetic acid (CDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), desferrioxamine, and ethylenediamine-N,N'-bis(2-dihydroxyphenylacetic acid) (EDDHA) were 55 to over 100% efficient in solubilizing equimolar amounts of Al. Tetracycline, EDTA, and 2,3-dihydroxybenzoic acid (DHBA) were less than 20% efficient. 1,4-Dioxane and fluoride were ineffective. The Do/w of Al averaged 0.005. The Do/w of the Al.chelator complex was generally less than that of Al, except for HBED and tetracycline (0.04 and 0.96, respectively). The Do/w of DHBA, desferrioxamine, EDDHA, and HBED were not influenced by Al, but tetracycline became more lipophilic. These compounds were tested for their ability to increase urinary Al excretion in Al-loaded rabbits. Chelators were given po weekly beginning 2 weeks after Al loading. Urine was obtained hourly from 3 hr prior to 6 hr after chelator administration and analyzed for Al. Fluoride and tetracycline (450 and 4500 mumol/kg) and citrate, NTA, EDTA, CDTA, DTPA, DHBA, HBED, and 1,4-dioxane (150 and 1500 mumol/kg) were ineffective. Following HBED administration, some of the Al-loaded rabbits died, presumably due to redistribution of Al within the rabbit. Following DTPA administration, some of the Al-loaded rabbits died, presumably due to DTPA. Oral EDDHA (1500 mumol/kg) significantly increased urinary Al excretion. EDDHA and desferrioxamine (150 mumol/kg) were administered by po, sc, and iv routes and were found to have comparable potency. The in vitro results may explain some of the in vivo findings. The in vitro methods may be useful to screen out compounds with no chelation potential. EDDHA-like compounds may have potential as alternatives to desferrioxamine in the prevention or treatment of Al accumulation and Al-induced toxicity.     

Acute zinc intoxication: comparison of the antidotal efficacy of several chelating agents

Four zinc compounds (acetate, nitrate, chloride and sulfate) were administered po or ip to rats and mice. The LD50 values were determined. Animals were observed for 14 days. The majority of deaths occurred during the first 48 hr. The clinical and physical signs appearing after intoxication included miosis, conjunctivitis, decreased food and water consumption and hemorrhages and hematomas in the tail. These changes decreased with time which would suggest a quick elimination of zinc. To determine the effect of 6 chelating agents on the toxicity of zinc, various doses of zinc acetate (66-330 mg/kg) were given ip to male mice followed by the injection of one of the chelators. DTPA, D-PA, CDTA and EDTA were the most effective. CDTA and DTPA were also the most effective in increasing the urinary excretion of zinc. DTPA appears to be the most effective agent of those tested in the prevention of acute zinc intoxication. However, CDTA may be considered as a possible alternative.     

Antidotes for zinc intoxication in mice

Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute zinc acetate intoxication in mice after i.p. administration. For a i. p. dose of 0.49 mmol/kg (LD₅₀) of zinc acetate, the i. p. administration of chelating agents at a 21 and 51 mole ratio resulted in a significant antidotal action for EDTA, DTPA, CDTA, d-penicillamine (d-PA), DMPS and DMSA. EGTA, l-cysteine, triethylentetraamine (TTHA), N-acetylcysteine (NAC), 4,5-dihydroxi-1,3-benzenedisulfonic acid (Tiron), sodium salicylate, glutathione, sodium diethyldithiocarbamate (DDC), 6-mercaptopurine and N-acetyl-d, l-penicillamine (NAPA) were not effective for acute zinc acetate poisoning. The therapeutic indices and therapeutic effectiveness of the most effective chelators were, respectively: EDTA (5.0, 7.0), DTPA (7.3, 13.7), CDTA (8.6, 6.3), d-PA (4.6, 1.9), DMPS (1.3, 1.0), DMSA (3.2, 5.4). DTPA, CDTA, and EDTA appear to be the most effective agents of those tested in offsetting acute zinc intoxication in mice.     

Chelation in Metal Intoxication. III. Lowering of Nickel Content in Poisoned Rat Organs

Abstract Six metal binding agents were screened in vivo for their ability to mobilise nickel from the brain, heart, kidney and liver of nickel poisoned rats. Out of these, 1,2 cyclohexylene dinitrilotetraacetic acid (CDTA) was most effective in removing the metal from the heart (78 %) followed by brain (76 %), kidney (65 %) and liver (57 %) whereas diethyl-dithiocarbamate (DDC) was more effective in the order of heart (85 %), liver (51 %), kidney (44 %) and brain (32 %). Under in vitro conditions, CDTA, diethylene triaminepenta-acetic acid (DTPA) and nitrilotriacetic acid (NTA) were found to be more effective in dialysing out nickel from the subcellular fractions of liver and kidney and the blood corpuscles of rats prctreated with nickel sulphate. In general, no correlation between the chemical structure or molecular weight of the chelators and their ability to remove nickel from the biological system was observed.     

Chelation in metal intoxication IX. Influence of amino and thiol chelators on excretion of manganese in poisoned rabbits

The effect of two polyamino-polycarboxylic acids, N-(2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA) and diethylenetriamine penta-acetic acid (DTPA) and two thiol-chelating agents, sodium diethyldithiocarbamate (DDC). and dimercaptosuccinic acid (DMS) on the excretion of manganese (Mn) in rabbits given Mn i.p. was studied in order to investigate the affinity of this metal to N,O and S-containing compounds. HEDTA and DTPA were effective, and DDC and DMS were ineffective, in enhancing urinary and faecal excretions of Mn, indicating a greater binding capacity of Mn with chelators having N and O, than with those having S as electron donating centres.     

Comparison of the effectiveness of several chelators after single administration on the toxicity,excretion and distribution of cobalt

The effects of the chelating agents Na₂Ca-ethylendiaminetetraacetate (EDTA), Na₃Ca-diethylentriaminepentaacetate (DTPA), L-cysteine, 2,3-dimercaptosuccinic acid (DMSA), N-acetyl-L-cysteine (NAC), glutathione, D,L-penicillamine (D,L-PEN) and 2,3-dimercaptopropanol (BAL) on the toxicity, distribution and excretion of intraperitoneally injected cobalt were studied in male Swiss mice. To determine the effect of the various chelators on the toxicity of cobalt, various doses of CoCl₂ (0.60–1.80 mmol/kg) were given, followed immediately by the IP administration of the chelator (at a dose equal to one-fourth of their respective LD₅₀). EDTA and DTPA were the most effective. EDTA, DTPA and L-cysteine, NAC and glutathione were also the most effective in increasing the urinary excretion of cobalt and reducing the concentration of the metal in various tissues. EDTA appears to be the most effective agent of those tested in the prevention of acute cobalt intoxication.     

Treatment of experimental acute uranium poisoning by chelating agents

Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute uranyl acetate intoxication in mice after subcutaneous administration. Chelators were administered intraperitoneally to male Swiss mice at a dose equal to one-fourth of their respective LD50 and the therapeutic effectiveness was calculated. Eight compounds resulted in a significant enhancement of the survival rate: Tiron, gallic acid, DTPA, p-aminosalicylic acid, sodium citrate, EDTA, 5-aminosalicylic acid and EGTA. Therapeutic indices (TI) were then determined for these chelating agents. Tiron (TI: 158), gallic acid (TI: 116) and DTPA (TI: 44.9) were the most effective antidotes. In subsequent experiments, uranyl acetate dihydrate was administered subcutaneously (10 mg/kg) in a 24 hr excretion and distribution study. The previous eight chelators were given intraperitoneally ten min. after the uranium administration. 5-Aminosalicylic acid and tiron were consistently the most effective in increasing the urinary and faecal excretion of uranium respectively. A decrease of the uranium concentration in kidneys and bone was also noted with tiron. Tiron appears to be the most effective agent of those tested in the prevention of acute uranium intoxication.     

Isolated rat hepatocytes as a model system for screening chelators for use in cadmium intoxication

The utility of isolated rat hepatocytes as a model system for screening potential chelators in treatment of Cd intoxication was studied. The ability of the chelators diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 2,3-dimercaptosuccinic acid (DMSA), diethyldithiocarbamic acid (DDC), d,1-penicillamine (PEN), nitrilotriacetic acid (NTA), and 2,3-dimercaptopropanol (BAL) to decrease the cellular concentration of Cd was correlated with the previously reported effectiveness of these agents in the treatment of Cd intoxication in vivo. The results of cellular studies with either control or metallothionein-induced hepatocytes were compared to the in vivo effect of the chelators administered before or after the induction of metallothionein, respectively. The effects of DTPA, EDTA, DDC, and BAL in the hepatocyte model screening system correlated well with their reported in vivo effects. The results with NTA, PEN, and DMSA were not correlated as well but were explained by the relative differences between in vivo doses versus in vitro concentrations of the respective chelators. Therefore, the proposed model for screening potential chelators for use in cadmium intoxication appears to be a system which may prove to be an economical and rapid method to facilitate the search for efficacious chelators.     

Beneficial effects of zinc supplementation during chelation treatment of lead intoxication in rats

The ability of zinc to enhance the efficacy of commonly used chelating drugs in lead intoxication and to reduce the resulting zinc imbalance, was investigated in rats. The simultaneous zinc supplementation increased urinary lead elimination by calcium disodium ethylenediaminetetraacetate (Ca disodium EDTA) and 2,3 dimercaptosuccinic acid (DMSA). Combination therapy was also effective in potentiating the depletion of blood, hepatic and renal lead by calcium disodium EDTA and D-penicillamine (DPA), renal lead by DMSA and reversal of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity by calcium disodium EDTA and DPA. The body zinc status was also maintained as reflected by urinary, blood and tissue levels of zinc.     

Evaluation of LD50 of some polyaminocarboxylic acids used as chelating drugs in metal intoxication

The LD50 of the following metal-binding chelating drugs, EDTA, diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), cyclohexanediaminotetraacetic acid (CDTA) and triethylenetetraminehexaacetic acid (TTHA) was evaluated in terms of mortality in rats after intraperitoneal administration and was found to be in the order: CDTA greater than EDTA greater than DTPA greater than TTHA greater than HEDTA. A possible correlation between the toxicity and molecular structure of the compounds is discussed.     

Influence of metal chelators on metalloenzymes

The influence of chelating agents (1 mmol/kg/day X 6,i.p.) on trace metal mobilization and activities of certain metalloenzymes was investigated in rats. Calcium disodium ethylenediamine tetraacetate (CaNa2EDTA) and calcium trisodium diethylenetriamine pentaacetate (CaNa3DTPA) enhanced urinary excretion of Zn, while sodium 2,3-dimercaptopropane-1-sulfonate (NaDMPS) and sodium diethyldithiocarbamate (NaDDC) increased that of Cu. The activity of Zn-metalloenzymes-blood delta-aminolevulinic acid dehydratase (delta-ALA-D), plasma alkaline phosphatase (ALP) and that of Cu-metalloenzyme-plasma amine oxidase was decreased as a consequence of chelation therapy. However, hepatic levels of delta-ALA-D, ALP and alcohol dehydrogenase remained unaffected by chelation. The activity of hepatic Fe-metalloenzyme-catalase was increased by polyaminocarboxylic acids and lowered by thiol chelators. The metal chelators decreased the hepatic glutathione levels.     

Chelation in metal intoxication. XIX. alpha-Mercapto-beta-aryl acrylic acid as antidotes to nickel and lead toxicity

In view of the reported effectiveness of alpha-mercapto-beta-(2-furyl) acrylic acid (MFA) as an effective antidote to inorganic mercury toxicity, some alpha-mercapto-beta-aryl acrylic acids were synthesized and examined for their efficacy in counteracting nickel and lead intoxication in rats. alpha-mercapto-beta-(3,4-dimethoxyphenyl)acrylic acid (MDA) was most effective and other compounds were less but about equally effective in enhancing urinary excretion and in reducing tissue concentration of Ni. MDA was the only compound to remove Ni from the brain. MFA was also more effective than other structurally related compounds in enhancing urinary and faecal excretion and in lowering body burden of Pb. All the compounds significantly reduced the inhibition of the activity of blood delta-aminolevulinic acid dehydratase (delta-ALA-D) and increase in the urinary excretion of delta-aminolevulinic acid (delta-ALA) caused by Pb. The results do not show any relationship between the nature of the substitution at the beta-position of alpha-mercapto acrylic acids and their ability to reduce the concentration and the toxic effects of the two metals. However, these thiol chelating agents appear promising as antidotes to Ni and Pb poisoning.     

五种螯合剂对大鼠体内微量元素影响的观察

观察了５种常用螯合剂对大鼠体内微量元素排出量、组织分布的变化。结果表明，５种螯合剂可不同程度地增加机体必需微量元素Ｚｎ、Ｃｕ、Ｍｇ和Ｃａ经尿液排出量。ＥＤＴＡ和ＤＴＰＡ的影响尤为明显。ＥＤＴＡ和ＤＴＰＡ可使Ｚｎ经尿液的排出量增加１６－５２倍，ＤＴＰＡ使肝脏Ｚｎ含量减少１５．９％（Ｐ〈０．０５），肝脏Ｃｕ含量下降６０％（Ｐ〈０．０５）。ＥＤＴＡ和ＤＴＰＡ注射后，肾中Ｚｎ含量明显增高，相当对照大鼠３．     

Pharmacokinetics of 2',3'-dideoxycytidine after high-dose administration to rats.

The pharmacokinetics of 2',3'-dideoxycytidine (DDC) was characterized after iv administration of a high dose (500 mg/kg) of DDC to rats. The high dose was administered to optimally characterize plasma DDC concentration and urinary excretion rate versus time profiles. Drug concentrations in plasma and urine were determined by HPLC. Plasma DDC concentrations and DDC urinary excretion rates as a function of time were fitted simultaneously to a two-compartment model. Drug concentrations in plasma and urinary excretion rates declined in parallel with a terminal half-life of 1.29 +/- 0.07 h (mean +/- SD). Total, renal, and nonrenal clearances were 1.48 +/- 0.15, 0.73 +/- 0.38, and 0.75 +/- 0.36 L/h/kg, respectively. Renal clearance exceeds glomerular filtration rate in the rat, indicating that DDC undergoes active renal tubular secretion. The unbound secretory intrinsic clearance for DDC renal excretion was moderate, with a value of 0.4 L/h. The steady-state volume of distribution of DDC was 1.25 +/- 0.13 L/kg. Pharmacokinetic parameters after iv administration of 500 mg/kg of DDC were virtually identical to those reported previously after administration of 10-200 mg/kg of the nucleoside to rats. Thus, the disposition of DDC in the rat is independent of dose over a range of 10 to 500 mg/kg. High doses of DDC can be administered to rats to allow for complete characterization of the disposition pattern of the drug without complexities due to any nonlinearity.