Toxicology and Applied Pharmacology 34, 259-263 (1975)
Influence of Chelating Agents on the Gastrointestinal Absorption
Of Lead,
SLOBODAN JUGO, TEA MALKOVIC, AND KRISTA KOSTIAL
Department for Mineral Metabolism, Institute for Medical Research,
Zagreb 41000, Yugoslavia
Received February 26, 1975; accepted May 16, 1975
Influence of Chelating Agents on the Gastrointestinal Absorption of Lead. Jugo, S., Maljkovich, T. and Kostial, K. (1975). Toxicol. Appl. Pharmacol. 34, 259-263. The effect of chelating agents given orally and parenterally in the therapeutic doses (02. mmol/kg) on the gastrointestinal absorption of lead (50mg/kg and 0.5 mg/kg) was investigated in female, 5- to 7- week-old rats using a method of radioactive 203Pb labeling. Intraperitoneal administration of calcium disodium ethylenediaminetetraacetate, and 2,3-dimercaptopropanol. given orally caused an increase in the lead absorption from the bowel. The amount of lead retained in the body in this experiment was also increased by all chelating agents except calcium disodium ethylene diaminetetetra acetate.
Despite some findings (Castellino and Aloj, 1965; Garber and Wei, 1974), it is generally accepted that the oral administration of calcium disodium ethylenediaminetetraacetate (Ca-EDTA) can increase the absorption of lead from the intestine (Rieders, 1960; Byers, 1959; Kehoe, 1955; Chisolm, 1968) by forming a Pb-EDTA chelate that is readily absorbed (Selander, 1967). Byers (1959) suggested that even the intravenous administration of Ca-EDTA may promote lead absorption from the bowel and, therefore, emptying the intestinal tract by enemata may be an important preliminary to treatment with chelating agents in acute oral lead intoxications. Catsch (1961) also indicated that the parenteral injection of chelating compounds can increase the intestinal absorption of metals since an increased resorption of radiometals from contaminated wounds after Ca-EDTA treatment was observed. It was experimentally shown that parenteral administration of chelating compounds can increase absorption of iron (Nigrovic et al,, 1967) and strontium (Kostial et al., 1967) from the intestine. However, there are no experimental data about increased intestinal lead absorption after a parenteral injection of chelating agents and thus it was proposed not to waste time with an enema and to institute chelation therapy as soon as possible (Chisolm, 1968).
* * * * *
. . . it was suggested that the biliary excreted fraction of the parenteral dos of chelating compounds may chelate lead intraluminally in the bowel and thus promote absorption (Jugo, 1973). To support this presumption it was necessary to show experimentally that lead in chelated form is much more readily absorbed form the bowel than unchelated lead. Therefore, a second experiment was performed and the results are presented in Table 2. All lead chelates were absorbed in greater amounts than the unchelated lead (p<0.001). All chelating agents, except Ca-EDTA also caused an increase in the whole-body retention of lead (<0.001). The amount of lead retained in the body after oral Pb-EDTA was not significantly affected. The urinary excretion of 203Pb was markedly enhanced in all groups receiving chelating agents (p<0.001).
DISCUSSION
In the first experiment (Table 1) we showed that the parenteral application of chelating agents such as Ca-EDTA and BAL can increase intestinal lead absorption. Thus the presumptions of Byers (1959) and Catsch (1961) were experimentally demonstrated. The mechanism of this action of the chelating compounds is not clear. One of the possible mechanisms could be stated as follows: A certain quantity of the parenteral dose of chelating agents is excreted by the biliary tract. The presence of the chelating agent in the intestinal content would result in the chelation of unabsorbed lead. [EDITOR’S NOTE: The concurrent administration of chelating agents whose function is limited to chelating within the intestinal tract, such as alginates, are the clearly highly desirable to minimize the possibility.] If the chelated lead is absorbed more readily than the unchelated lead, the intestinal absorption of lead will increase. Such a mechanism could explain the effect of BAL but is less likely to in the case of Ca-EDTA. Namely, BAL is eliminated rapidly by the biliary and urinary tract (Peters, et al., 1953) and such a small quantity of Ca-EDTA could provide a means for increase of lead absorption only if the absorbability of Pb-EDTA chelate is much greater than shown by our experiment (Table 2).
A nonspecific increase in intestinal permeability after Ca-EDTA treatment had been reported (Aronson and Rogerson, 1972: Schanker and Johnson, 1961) but the doses that were used were toxic and much higher than those used here.
Although the mechanism of such action remains to be elucidated, the increased absorption of lead from the intestine induced by the parenteral injection of chelating agents may explain the clinical experience of deterioration in some cases of lead encephalopathy after chelation therapy has been instituted (Chisolm, 1968). According to our results, this phenomenon may be related to enhanced intestinal lead absorption with an elevation of circulating lead concentrations and consequent toxic effects. It is concluded that in acute oral lead intoxication, especially if it is severe, the use of an enema for removal of unabsorbed lead from the bowel before instituting chelating agents may be an essential step in the therapeutic regime.
In the part of this work that dealt with the influence of oral chelating agents on gastrointestinal lead absorption, we showed that all chelating agents used enhanced the amount of lead absorbed. This finding is of considerable importance since the intestinal tract is a major route for burdening the human population with lead (National Academy of Sciences, 1972), and some chelating compounds are widely used as food additives or may occur as natural food constituents (Furia, 1968). Our results are in agreement with the recent report of Garber and Wei (1974) who found that sodium citrate increased the intestinal absorption of lead in mice. The same authors failed to find our effect of Ca-EDTA, probably because they neglected urinary excretion in calculating the amount of lead absorbed.
According to our results,
D-penicillamine which is used as an oral drug for lead poisoning (Selander, 1967; Goldberg et al., 1963; Chisolm, 1968) can enhance lead absorption and therefore we would like to recommend that oral D-penicillamine be avoided if a significant amount of unabsorbed lead in the bowel is suspected.
TABLE 1
INFLUENCE OF INTRAPERITONEAL ADMINISTRATION OF CALCIUM DISODIUM ETHYLENE-
DIAMINETETRAACETATE (EDTA) AND 2,3-DIMERCAPTOPROPANOL (BAL) IN EQUIMOLAR
CONCENTRATION (0.2 mmol/kg) ON ABSORBTION, WHOLD-BODY RETENTION, AND
TOTAL URINARY EXCRETION OF SINGLE ORAL DOSE OF 203PB GIVEN BY STABLE
LEAD (50mg/kg) ACETATEa
|
Number of Whole-Body Total Urinary Group Animals Retention Excretion Absorptionb |
|
Control 18 1.05 ± 0.14 0.13 ± 0.02 1.19 ± 0.15 Ca-EDAT 20 1.47 ± 0.24 1.54 ± 0.29 3.01 ± 0.50 BAL 20 1.60 ± 0.28 1.45 ± 0.24 3.05 ± 0.49 |
a
The results are expressed as percentage of dose (mean ± SE) 144 hr after lead and chelating agent administration.b
Absorption was calculated by adding total urinary excretion to whole body retention.
TABLE 2
ABSORPTION, WHOLE-BODY RETENTION, AND TOTAL URINARY EXCRETION OF 203PB,
144 HR AFTER A SINGLE ORAL DOSE OF SOME LEAD CHELATES TO RATSa
|
Number of Whole-Body Total Urinary Group Animals Retention Excretion Absorptionb |
|
Control 8 0.70 ± 0.15 0.31 ± 0.05 1.01 ± 0.20 (Pb-acetate) Pb-EDTA 10 0.43 ± 0.04 1.39 ± 0.13 1.82 ± 0.14 Pb-citrate 9 2.30 ± 0.48 0.61 ± 0.10 2.94 ± 0.57 Pb-penicillamine 7 1.87 ± 0.19 1.22 ± 0.10 3.09 ± 0.28 Pb-BAL 10 3.39 ± 0.44 6.62 ± 0.96 9.94 ± 1.31 |
aDose of stable lead was 0.5 mg/kg, and doses of chelating agents were 0.2 mmol/kg. The results are expressed as a percentage of dose (mean ± SE).
b
Absorption was calculated by adding total urinary excretion to whole body retention.
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