RT Journal Article SR Electronic T1 STUDIES IN THE ELIMINATION OF CERTAIN OF THE DIGITALIS BODIES FROM THE ANIMAL ORGANISM JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 405 OP 496 VO 12 IS 8 A1 ROBERT A. HATCHER A1 CARY EGGLESTON YR 1919 UL http://jpet.aspetjournals.org/content/12/8/405.abstract AB The fatal intravenous dose of ouabain for the rat depends somewhat on the rate of injection, but with the rapid injection of a solution of one part in two hundred parts of normal saline the average is approximately equal to 12 mgm. per kilogram of weight. Ouabain leaves the blood stream rapidly, and after a few minutes not more than a trace—too small to be detected by our method—is present in the blood of the rat. Much the larger proportion of an intravenous dose is fixed in the liver at once, or very shortly after the injection, and a smaller part is fixed in the kidney. It is loosely bound in the vessels of the liver at first (and probably in those of the kidney) and then it may be removed by simple perfusion with normal saline; it appears to pass from the vessels into a more stable combination presumably in the cells of the liver (and in those of the kidney), it passes fairly rapidly from the cells of the liver into the bile ducts and thence into the duodenum; it is extracted easily after it passes into the bile ducts. After ouabain passes into the duodenum of the rat a variable amount is destroyed in the large intestine, but a part of even so little as may be injected intravenously without causing death, may traverse the intestine and appear in the feces, while equal percentages of many times larger amounts may be destroyed, after the oral administration, in similar periods of time. When the bile duct is tied, preventing the ouabain from passing from the liver into the duodenum, it is reabsorbed from the liver into the blood, carried to the kidney and excreted quantitatively, or to a very great extent, in the urine. We have some evidence that a part of the poison injected intravenously is destroyed in the body, probably in the liver. The behavior of amorphous strophanthin and that of ouabain in the rat present many points of similarity. Both are absorbed very slowly and only to a slight extent from the gastro-intestinal tract, and the portions so absorbed are excreted in the urine in part, and in part by the liver presumably. They resist the action of the digestive ferments in the stomach and duodenum, but much the larger part of an oral dose is destroyed in the large intestine. Amorphous strophanthin is much the more toxic by intravenous than by subcutaneous injection in the rat; this difference is apparently due mainly to the slower fixation and excretion by the liver. A large part of an intravenous dose of amorphous strophanthin is fixed in the liver and excreted into the intestine; the kidneys probably excrete a larger percentage of a subcutaneous, than of an intravenous, dose, and as much as 65 per cent of a subcutaneous dose may appear in the urine. It is possible that a larger number of experiments might show that there is less difference in this respect than we have found. Tying the common bile duct increases the activity of amorphous strophanthin for the rat, probably because of the reabsorption into the circulation of a part of that which has been fixed in the liver, and which is then prevented from passing into the intestine. We have been unable to determine with certainty whether any part of an intravenous dose of amorphous strophanthin is destroyed in the liver or other organs of the rat, but such destruction seems probable. The close similarity in the behavior of ouabain and amorphous strophanthin in the body of the rat renders a more detailed consideration of our experiments with the latter drug unnecessary, because it would be mainly a repetition of what was said concerning the experiments with ouabain. The following refers only to the behavior of digitoxin in the rat. Digitoxin is absorbed from the gastro-intestinal tract far more readily than ouabain or amorphous strophanthin, though it is practically insoluble in water. The proportion of an oral dose of digitoxin that escapes destruction and appears in the feces varies widely in different experiments. Nearly all is destroyed in some, very little in others. This destruction is probably greater when loss of appetite prevents active intestinal peristalsis permitting a longer sojourn of the poison in the intestine. Much the larger part of an intravenous dose of digitoxin—90 per cent or more—leaves the blood within a period of five minutes. Part of the digitoxin injected intravenously is fixed in the liver, at least a part reaches the intestine, and a part may even appear in the feces. Much the larger part of a severely toxic intravenous dose is destroyed in the body. Digitoxin is not excreted by the kidneys of the normal rat except possibly in traces, and it is possible that somewhat larger amounts may appear in the urine after the bile duct is tied, but this remains to be determined. The action of a single toxic oral, subcutaneous, or intravenous dose of digitoxin is far more lasting than that of ouabain, but a very large amount of digitoxin may be survived following its subcutaneous injection in two doses administered within a short time. The toxicity of digitoxin for the rat is about the same as that of amorphous strophanthin by intravenous injection, it is far the more toxic with oral administration; far less with subcutaneous injection. These differences in the toxicity of the two poisons by different modes of administration depend on differences in their rates of absorption (except after intravenous injection) and elimination. The fatal intravenous dose of the most active available commercial digitalein for the rat is roughly 75 mgm. per kilogram; that by oral or subcutaneous injection is nearly ten times as much. Those constituents of digitalein that exert a true digitalis action leave the blood of the rat promptly, the digitonin constituent probably disappears much more slowly. We have no evidence that the constituents of digitalein having a true digitalis action are fixed in the liver of the rat, but the question remains open. Not more than traces of the true digitalis bodies of digitalein appear in the urine or feces after oral, intravenous, or intramuscular administration, hence they must be destroyed in the body. We have not determined the seat of this destruction in the normal animal, but since it occurs after the bile duct has been tied, it seems probable that the liver is the chief organ concerned in the destruction of that portion which enters the circulation; the large intestine is probably concerned with the destruction of the greater part of an oral dose. Ouabain disappears rapidly from the circulation of the cat and dog, less than 50 per cent of a massive intravenous dose being present in the blood at death, which occurs within two to three minutes. Small amounts of ouabain can be detected in the nearly bloodless liver after the administration of such doses, and after perfusion with diluted, defibrinated blood to which ouabain has been added. The participation of the liver is not essential for the rapid removal of ouabain from the blood, for it disappears almost as rapidly when the circulation is restricted to certain small areas, but not when it is limited to the heart and lungs. It is probable that small amounts of ouabain are excreted by the kidneys, but it cannot be detected in the urine of the cat or dog after the administration of sub-lethal doses, except possibly after copious diuresis. Ouabain cannot be detected in the bloodless voluntary muscle or brain after the intravenous injection of massive doses, or in those structures after perfusion with it. We can offer no other explanation of the rapid disappearance of large amounts from the blood than that the normal liver decomposes the poison more rapidly than the perfused liver, or, that the ouabain is widely distributed in various tissues of the body. If that part of the ouabain which leaves the blood before death were distributed nearly uniformly throughout the body, the amount present in any one tissue would be insufficient to permit of its extraction and estimation (owing to its dilution in the extract) with a sufficient degree of precision to permit of our determining whether it was present in the blood of the tissues or in the tissues themselves. Our inability to detect such amounts in extracts of the tissues will be understood when it is remembered that the fatal intravenous dose of ouabain for the cat is only equal to one-ten-millionth of the body weight.