The efficiency with which diodrast (3, 5-diiodo-4-pyridone-1-acetic acid) and hippuran (oiodohippuric acid) are excreted by the renal tubules (1, 2) raises the question to what extent the organically-bound iodine in these molecules is responsible for the phenomenon of tubular excretion. Since suitable quantitative methods for the determination of unsubstituted compounds wvere not available, substituted derivatives of hippuric acid which could be determined by appropriate coupling reactions were prepared 2 and studied under conditions permitting the exact comparison of renal clearances with those of diodrast atnd hippuran.Methods of comparing clearances. When two substances, both of which are excreted by the tubules, are presented to the tubular excretory mechanism simultaneously, one substance may depress the tubular excretion of the other (2, 3).3

It is a peculiar and interesting fact that marine teleosts excrete urine which is isotonic or hypotonic with respect to the blood, and therefore of considerably lower osmotic pressure than sea water (Rodier, 1899; Bottazzi, 1906; Dekhuyzen, 1905; Burian, 1908, 1910). From this, it appears that these animals are faced with the task of concentrating the surrounding ocean in order to obtain water for the formation of urine, a task which can only be performed at the expenditure of energy in osmotic work.' This circumstance might be expected to result in profound differences in the water economy of marine fish as compared with fresh water and terrestial animals to which water is available ad k&turn. The answer to the question of what tissue or tissues actually do the work of separating from the sea water the osmotically dilute solution destined to be excreted as urine appears to rest in the determination of whether the renally excreted water is initially absorbed from the intestine or enters the body through the gills. The work to be reported here leads us to the conclusion that water absorption occurs by way of the intestine; but, surprisingly, it is not in the intestine that the osmotic work is done, for the residue formed there as absorption proceeds is actually more dilute than the ingested sea water, and tends to approach the blood in tonicity. This osmotic dilution results from the fact that Na, K and Cl are absorbed from the intestine, along with a considerable fraction of the water, leaving behind only the poorly absorbed Mg and SO4 in highly concentrated state. During this process of concentration some Mg and SO4 are abosrbed, to be subsequently excreted in the urine. The bulk of the Na, K and Cl, together with the bulk of the water absorbed from the intestine, never appear in the urine, however; they are excreted by routes other than the kidneys-lThis problem was recognized by Dekhuyzen (1905) who remarks '(.. ,. . la richesse relative en eau de cette urine prove plutot que les poissons marine resorbent de l'eau, on si l'on prefer-e une solution diluie effectuant ainsi un travail contre la pression osmotique en consommant de l'energie chimique ." 480

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Although phlorizin has been used mostly in the lower animals, its administration to man is not without precedent; shortly after its isolation by de Koninck (1836a, b), this investigator tried it in the treatment of malaria on the ground that it was bitter, like other remedies which were effective in this disease. The use of the drug in this connection was short-lived, however, and it was not until many years later that v. Mering (1885) discovered that it caused glycuresis and diuresis, observations which initiated its application in the treatment of nephritis, sarcoma, etc., and as a test for renal function in man, in addition to its well known use in studies of metabolism. Since these instances of human administration are of some interest, we have summarized them in Table I Lewis (1913-personal communication) gave 2 grams daily in 10 cc. of sterile olive oil subcutaneously over a period of days. In no instance was permanent injury described.Moderate intravenous doses of the drug produce no unfavorable reactions in the dog, and we decided that the intravenous route would be the most satisfactory for our purposes, particularly since we wished to determine the exact effect of small doses. Our anticipation in this matter has been justified, since we have given phlorizin in doses varying from 2.0 to 65.0 mgm. per kgm. with no unfavorable reactions other than an apparent diminution in glomerular activity with the larger doses. We feel called upon, however, to express a word of caution about the use of the intravenous technique in man and refer the reader to the description of our method of preparation and administration. Previous observations from this laboratory have shown that in the dog adequate doses of phlorizin raise the glucose clearance and lower the creatinine clearance to the level of the xylose clearance (Jolliffe, Shannon and Smith 1083