THE METABOLISM OF C14 LABELED ETHYLENE DIAMINETETRA-ACETIC ACID IN HUMAN BEINGSLife Flow One by |
J. Lab. & Clin. Med.
THE METABOLISM OF C14 LABELED ETHYLENEDIAMINETETRA-ACETIC ACID IN HUMAN BEINGS
Harry Foreman, M.D., Ph.D., and Theodore T. Trujillo, B.S.
Los Alamos, N.M
E
THYLENEDIAMINETETRAACETICacid is a recently developed therapeutic agent used in the treatment of lead, and radioactive metal poisoning, as an anticoagulant in blood used for transfusion, and in other instances where control and investigation of metal ion concentration is desired. A study of the metabolism of the compound was undertaken to gain information which might be used for more effective application of the material, in particular for establishing optimum dosage schedules, and to reveal any possible deleterious effects which might result from prolonged use of the drug. The calcium chelate of the compound was studied since this is the form in which the drug is most commonly employed. METHODSYoung adult healthy mend were used as subjects. Studies were carried out after intravenous, intramuscular, and oral administration and after application on the skin. Three subjects were used in each group.
In the intravenous studies, the injection solution was prepared by mixing 2.2mg of CA ethylenediamine-2-C414 acetic acid, yielding approximately 2.5 x 107 disintegrations per minute (d/m) with 2 GM. Of "cold" (unlabeled) CaNa2EDTA* in a total of 10.5ml of water solution. The C14 labeled material was prepared by Murray and Ronzio. The "cold" CaNa2 EDTA was prepared as a 20 percent neutral solution in water, especially for drug use. The injections were given over two-to-three-minute periods into the antecubital arm vein. Blood samples were drawn at appropriate intervals indicated in Fig. 1, and in once case a spinal fluid sample was obtained. Urine was collected as voided for twenty-four hours, at which time the activity had fallen below detection levels. In two of the intravenous studies blood pressure readings and four-lead electrocardiogram tracings were made every fifteen minutes starting on-half hour before the administration of dose and continuing for an hour after. This was done to determine any cardiovascular changes brought about by the drug.
The dose for intramuscular studies consisted of 2.2mg C14 labeled Ca EDTA mixed with 1 GM. "cold" Ca EDTA and 2ml of 1 percent procaine solution, all made up to 10ml with water. Injections were made into the buttocks, 5ml on each side. Blood and urine samples were collected as in the intravenous studies. Feces were not collected since pilot studies indicated 85 to 89 percent of the activity could be recovered in the urine.
For oral administration, 1.5mg of C14 labeled Ca EDTA yielding approximately 1.6 x 107 d/m was dissolved in one-half ml. Of water and given a gelatin capsule. Urine and feces were collected for assay. Blood samples were drawn in the first study but it was found that the level of activity was too low to measure and hence this was not done in subsequent studies.
* * * * *
. . studies in which blood pressure, pulse, and electrocardiograms were followed
before and after intravenous injection of the drug, no unusual cardiovascular
changes could be detected
DISCUSSION
The appearance of over 95 percent of the injected activity in the urine and the identification of this activity as labeled Ca EDTA indicate that the metabolism of the compound is singularly uncomplicated; namely, that it passes the kidney. It appears that the only interaction in the body is combination with certain di- and tetravalent metal ions and that any therapeutic or deleterious effects occur solely via this mechanism. Because of the rapid and complete elimination of the drug, the only likely long term deleterious effect from prolonged administration one might consider, is a slow depletion of the body of an essential ion, perhaps iron, cobalt, or manganese, etc. This possibility is not answerable by the present study.
Consideration of the blood clearance curves shows that shortly after parenteral administration the drug leaves the blood and mixes with a large volume of tissue fluid, namely from 40.8 to 47.6 liters* in the various individuals studied. These figures represent from 58.2 to 68 percent of the body weights of the subjects, which is approximately the entire body water. The material, however, must not mix with all of body water initially since, as seen from Table II, it does not enter the red cells, and, as seen from the spinal fluid study, it passes very slowly across the blood-spinal fluid barrier.
Renal clearance, determined from the equation C == 0.693
V,where C == renal clearance, T½ == half time of blood clearance, and V == the dilution volume (see Forman, Vier, and Magee,), gives a value for the intravenous study of 680ml. Per minute which indicates the material is cleared by tubular excretion as well as by glomerular filtration. The rapid turnover time suggests that frequently repeated doses will be required to maintain blood levels, unless some device for slow continuous release of the material into the blood stream is used.
The low absorption after oral administration is very surprising in view of the finding that the material is effective by that route in accelerating the excretion of yttrium2 and lead.1 There is no satisfactory readily apparent explanation of this at present. [Emphasis added.]The lack of absorption across the skin likewise was surprising. It was expected this would be appreciable in view of the findings of Povichi and co-workers which indicated there was a fall in serum calcium levels after application of the drug to the skin.
SUMMARY
This study in human beings using C14 labeled material indicates that Ca EDTA passes through the body unchanged. It is excreted via the kidney by both glomerular filtration and tubular excretion. The turnover time from the blood is approximately one hour after intravenous administration and one and a half hours after intramuscular injection. It quickly mixes with almost all of the body water except that it does not pass into the red cells and passes relatively slowly into the spinal fluid compartment. It is poorly absorbed from the gastrointestinal tract (a maximum of 5 per cent) and practically not all through the skin. The use in therapeutic doses did not bring about any unusual cardiovascular changes in the cases studied.
We wish to express thanks to Ernest Anderson, Samuel Rothermel, and Thomas Moore for their aid in this work._____________________________________________________
References
1. Rubin, M., Gignac, S., Bessman, S.P., and Belknap, E.L:
Enhancement of Lead Excretion in Humans by Disodium Calcium Ethylenediamine
Tetraacetate, Science 117: 659, 1953.
2. Sulbury, J.B., Jr., Bynum, J.L., and Fetz, L.L: Effect of Chelating
Agent on Urinary Lead Excretion, Proc. Soc. Exper. Biol. & Med. 82:266,
1953.
3. Foreman, H: The use of Chelating Agents for Accelerating Excretion of
Radioelements, J. Am. Pharm. A. (Scient. Ed.) 42:629, 1953.
4. Proescher, F: Anti-Coagulant Properties of Ethylene Bis-iminodiacetic
Acid, Proc. Soc. Exper. Biol. & Med., 76:619, 1951
5. Spencer, H., Vankinscott, V., Lewin, I., and Lazlo, D: Removal of
Calcium in Man by Ethylenediamine Tetraacetic Acid, J. Clin. Invest. 31:1023,
1952.
6. Murray, A., III and Ronzio, A.R.: The Synthesis of Ethylenediamine
Tetra-(2-C414 Acetic) Acid, J. Am. Pharm. A. (Scient. Ed.)
41:596, 1952.
7. Consden, R., Gordon, A.H. and Martin, A.J.P: Parition Chromatography
With Paper, Biochem. J. 38:224, 1944.
8. Foreman, H., Vier, M., and Magee, M: The Metabolism of C14
Labeled Ethylenediamine Tetraacetic Acid in the Rat, J. Biol. Chem. 203:1045,
1953.
9. Popovici, A., Geschickter, L.F., Reinovsky, A., and Rubin, M:
Experimental Control of Serum Calcium Levels in Vivo, Proc. Soc. Exper. Biol.
& Med. 74:415, 1950.
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