Evan W. McChesney

ABSORPTION, EXCRETION, AND METABOLISM OF A NEW ANTIBACTERIAL AGENT, NALIDIXIC ACID.

Abstract Studies of the absorption, excretion, and metabolism of a new antibacterial agent, nalidixic acid, have been made. The compound is rapidly absorbed when given in capsule or tablet form, as the free acid; it is excreted in the urine by man, partly in the free (extractable, biologically available) form, but a much larger fraction as a monoglucuronide, and a considerable fraction is converted to the 7-hydroxymethyl metabolite. A lesser amount of the latter is also excreted in a conjugated form, and a rather minor excretion product is the 3,7-dicarboxylic acid. The conversion of nalidixic acid to conjugated and hydroxylated forms appears to begin almost immediately upon absorption. Of single or repeated oral doses, about 80% of nalidixic acid is recoverable from the urine as definitely characterized products; fecal excretion is of minor importance, although the drug does appear in the bile of monkey and dog. Supplementation of nalidixic acid medication with bicarbonate greatly increases the amount of naphthyridine excreted in the urine in a biologically available form (i.e., the unconjugated forms of nalidixic acid and its hydroxymethyl metabolite). The excretion of the hydroxymethyl metabolite when administered as such follows much the same general pattern as that of the parent compound. However, the former compound has less tendency to conjugation and bicarbonate supplementation further decreases the extent of conjugation to the point where nearly half of the orally ingested metabolite may appear in the urine in a biologically available form. When studied in dogs and monkeys following long-term administration at high dose levels, nalidixic acid is found to have little tendency to accumulate in any tissue; practically all tissues have lower concentrations than those existing concomitantly in the plasma. The highest tissue concentrations relative to plasma, in both species, are in kidney, and the lowest are in brain and fat.

Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats

Abstract The administration of chloroquine or hydroxychloroquine to albino and pigmented (hooded) rats at a daily dosage of 40 mg/kg produces a rapid rise in tissue concentrations of the drugs during the first month of medication, but comparatively little further rise when the medications are continued for two additional months. The mean tissue concentration of chloroquine at 1 month is about 100 mg/kg, compared to about 30 mg/kg for hydroxychloroquine. However, rats degrade the latter compound more extensively, so that their total mean tissue content of 4-aminoquinoline bases is greater than 30 mg/kg at that time. The order of increasing tissue concentration for both drugs is almost invariably: muscle, eye, heart, kidney, liver, lung, and spleen. In the pigmented rats, the order is: muscle, heart, kidney, liver, lung, spleen, and eye. When medication is discontinued, the concentrations of both drugs in the tissues decrease very rapidly, except in the eyes of the pigmented rats. Long-continued exposure of the eyes of the pigmented rats to high concentrations (approaching 0.1%) of chloroquine or hydroxychloroquine and their degradation products does not produce any detectable ocular histopathology.

Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat

Abstract Chloroquine was administered to albino rats in the diet for 32 weeks at levels estimated to provide daily intakes of 1.9, 5.6, or 16.8 mg/kg. At the conclusion of the experiment the amount of drug retained in the tissues analyzed ranged from 28 to 37% of the intake for 1 day, and the order of increasing tissue concentrations was: muscle, eye, heart, liver = lung, kidney, and spleen. Hydroxychloroquine was similarly administered to albino rats for 30 weeks at levels estimated to provide daily intakes of 7.8, 19.4, or 48.4 mg/kg. At the conclusion of the experiment the amount of HCQ retained in the tissues ranged from 22 to 31% of the intake for 1 day and the order of increasing concentrations was generally: muscle, eye, heart, kidney, liver, lung, spleen. Chloroquine and desethylchloroquine were administered to albino and pigmented rats (by stomach tube) at a dosage of 40 mg/kg/day of base, 6 days per week for one month. Twenty-four hours after the last dose these animals also retained in the tissues analyzed amounts of these drugs equivalent to about 33% of one daily dose. The order of increasing tissue concentration of CQ in both strains at this time was essentially the same as previously reported (McChesney et al., 1965) except for a reversal of the positions of liver and lung. The order of increasing tissue concentration of desethylchloroquine in both strains was much the same as for chloroquine; i.e., in the albinos it was muscle, eye, heart, kidney, lung, liver = spleen; while in the pigmented rats it was muscle, heart, kidney, lung = liver, spleen, eye. The decrease in tissue concentrations of chloroquine following discontinuance of medication indicated a half-life of 1.5 days, while the corresponding data for desethylchloroquine indicated a half-life of 2.3 days. Tissue concentrations of both of these drugs were generally higher in the females than in the males, but in the case of chloroquine the difference was much more marked.

The hyperglycemic action of some analogs of epinephrine.

Conclusions Of the several compounds tested, only 1-arterenol has a hyperglycemic action of the same order as that of 1-epinephrine. Its activity can be placed at about 1/8 of that of epinephrine, while the d-isomer has about 1/20 of the activity of the l-isomer. Sahyun14 found that dl-arterenol, 1 mg/kg, produced an average rise iin blood sugar of 78 mg%percnt; 3 hrs after subcutaneous injection in 7 rabbits. This is considerably more activity than would be calculated from our observations on the separate isomers. However, if one of his rabbits (No. 8, Table II) is eliminated from consideration, the average rise becomes only 61 mg%percnt;, and the discrepancy is much less. Of the other compounds studied, Isuprel is clearly the least active. The approximate hyperglycemic activity of the whole series of compounds, taking l-epinephrine as 100, is as follows (all figures given have been calculated in terms in terms of the free base): l-arterenol, 12; Win 3046, 1.7; Butanefrine, 1.6; Win 515, 0.7; d-arterenol, 0.6; and Isuprel, 0.12.

Metabolism of chlormezanone in man and laboratory animals

Abstract The metabolism of chlormezanone has been studied in rats, dogs, and man. After oral administration to the rat, the tissue : plasma concentration ratios are very close to unity, and the mean decrease in concentrations between 2 and 4 hr postmedication is about 30 per cent. In the dog, an oral dose of 7 mg/kg gives a peak plasma level of 5–6 μg/ml, while 200 mg/kg gives a peak level of 140–160 μg/ml. The plasma half-lives for these doses, however, are quite different: about 4 and 12 hr respectively. One hr after the intravenous administration of 25 mg/kg to dogs, the plasma level is about 30 μg/ml, and the regression rate indicates a plasma half-life of 10 hr. In man a single 400-mg dose gives a peak plasma level of 5–6 μg/ml, with an indicated plasma half-life of 24 hr. The use of a simple first-order absorption and elimination model has permitted the calculation of a human dosage schedule designed to maintain the plasma level almost constantly between 5 and 10 μg/ml, and this schedule has been verified experimentally. Chlormezanone is excreted as such in human urine and dog bile. Its ingestion by man results in the excretion of no extra glucuronic acid but does lead to the excretion in the urine of an acid which is evidently 4-chlorohippuric. It appears, therefore, that the degradation of chlormezanone in man may be explained largely on the basis of a nonenzymatic hydrolysis, followed by oxidation and conjugation of the 4-chlorobenzaldehyde formed in the hydrolytic reaction.

SOME ASPECTS OF CATION EXCHANGE RESINS AS THERAPEUTIC AGENTS FOR SODIUM REMOVAL

Since Dock’s publication in 1946,’ about fifty papers dealing with the use of cation exchange resins for restricting sodium absorption have appeared.2 Approximately 7.5 per cent of these papers have dealt with studies in human subjects and, as a result, the potentialities, limitations, and hazards4, of the procedure are quite well defined. I t is clear that a valuable therapeutic medicament, although one which requires thorough understanding if it is to be effectively and safely used, has become available. Several typesa of exchange resins can be employed to produce changes in cation metabolism. These resins differ with respect to both matrix and functional groups. Two types of functional groups, the sulfonic and the carboxylic, have been extensively studied in this connection. I t is the object of this paper to discuss critically the inherent differences in behavior of these two materials, specifically: (1) their relative efficiency in the removal of sodium from the alimentary canal; (2) the effect of the sodium and potassium levels in the diet on their cation uptake; and (3) other considerations related to their therapeutic usefulness. If one sets out to evaluate a new therapeutic agent, the chronic toxicity problem must be taken into account. We have carried out in our laboratories an extensive long-term feeding experiment in addition to many short-term studies. FIGURE 1 shows growth curves of some of the animals on the longterm experiment, up to and including its 65th week. This is a length of time which represents approximately one-third the life span of the rats. The results indicated no significant decrease in the rate of growth at resin levels of 10 per cent of the diet. A comparison of in vivo uptake of sodium, potassium, and total alkali metal ions by sulfonic and carboxylic resins is shown in TABLE 1. I t indicates a 25 per cent better average uptake by three sulfonic preparations than with the three carboxylic formulations. It also shows about equal potassium removal, and a better selectivity coefficient of the sulfonic type for sodium. Much has been said about the higher in witro capacity of the carboxylic resins (about 12 meq./g.) in contrast to the sulfonic types (about S meq./g.). It should be remembered, however, that the full capacity of the carboxylic types is realized only at pH values above 10, due to the weak ionization constant of the functional group. Under physiological conditions this high ‘‘ theoretical” capacity is not available. Hence, an efficiency ratio, which we could define as the in vivo capacity for sodium plus potassium divided by the maximum theoretical capacity, yields values of 0.33 and 0.11 for the two types, respectively, i .e. a greater efficiency or saturation of the sulfonic resin. The same conclusion with respect to superiority of sulfonic over carboxylic resins as therapeutic agents was reached by Herken and Wolf,3 who stressed the ad-

Urinary Excretion of Three Oral Gholecystographic Agents in Man

Summary The excretion of 3 oral cholecystographic agents in the urine has been studied in 3 normal subjects in experimental cross-over design, following administration of standard diagnostic dosages. For the 0-108-hour period the total mean excretion, based on organic iodine determination was: for iopanoate, 1.1 g (37%), for tyropanoate 2.2 g (49.9%), and for bunamiodyl, 2.0 g (44.2%). For all 3 compounds less than 8% of the urinary iodine was in a solvent-extractable (presumably unchanged) form. In view of the relatively small amounts of the radiopaques excreted in the urine in an unchanged form, and their solubilities at physiological pH values, it does not appear that renal damage due to actual physical blockage should represent a significant hazard. Nevertheless, the suggestion of Nelson(14) that these compounds should be accompanied by an adequate fluid intake seems in order.

Absorption, Excretion, and Toxicity of Milibis (Bismuthoxy-p-N-glycolyl-arsanilate) Following Oral Administration

Summary Milibis is almost completely non-toxic when administered orally to rats. A dose of 10 g/kg/day for 18 of 21 days inhibited growth only slightly, and at this dose level the mortality was 20%; with smaller doses there was no inhibition of growth, and no mortality attributable to the drug. Absorption was studied in human subjects and rats, during and following repeated oral administration. Both species excreted in the urine at most 2 to 4% of the ingested As. Human subjects excreted no detectable Bi in the urine, but the rats excreted about 1% of the amount ingested. In the rats tissue concentrations of both As and Bi were negligible, as was the As concentration in blood.

Role of Inositol and p-Aminobenzoic Acid in Normal Lactation

Conclusions The results indicate that the B-complex supplement without p-amino-benzoic acid or inositol will not support normal lactation, that under these conditions the initiation of lactation is slow, and that it never achieves a normal level. The rapid decline in milk production beginning with the tenth postpartum day is also noteworthy; it culminates in almost complete cessation of lactation on the 14th day. The addition of p-aminobenzoic acid to the B-complex supplement appears to result in delayed initiation of lactation, there being no significant amount of milk until the 5th post-partum day. After this time, however, secretion was maintained at a normal level. With the addition of inositol to the B-complex supplement there was a prompt initiation of lactation which was maintained at a level only slightly less than that of the controls. Further supplementation of this regime with p-aminobenzoic acid resulted in no significant improvement in milk secretion over that in the group which received the B-complex supplement and inositol alone. These findings are in general supported by the infant mortality rates for the various experimental groups. From these data we may conclude that the B-complex supplement alone or with the addition of p-aminobenzoic acid will not support normal nutrition of young rats. Supplementation with inositol results in mortality rates only slightly greater than those observed in the control animals. Supplementation with both inositol and p-aminobenzoic acid results in mortality rates quite comparable to those of the controls. Summary. The critical role of inositol in the maintenance of normal lactation in the albino rat has been confirmed. P-aminobenzoic acid does not seem to increase lactation directly but when given to animals also receiving inositol it slightly decreases mortality rates of the newborn.

Toxicity and physiological disposition of sodium p-N-glycolylarsanilate

Abstract The acute intravenous LD 50 of SNGA to mice has been established as 5850 ± 360 mg/kg, and the oral LD 50 as 22500 ± 1540 mg/kg, based on deaths within 24 hours. The acute ALD 50 for the cat is 1060 mg/kg. SNGA is only slightly absorbed from the digestive tract of the rat; urinary excretion is 5–10%, and fecal excretion is 90–95% of the dose, following oral administration. Following parenteral administration to cat or rat, the urinary excretion is about 75% of the dose (for the limited periods of observation used). Biliary excretion in the cat is only about 1% of the dose, following i.v. administration, and fecal excretion in the rat following i.p. administration is 3–7% of the dose. Some of the parenterally administered arsenical is retained in the blood of the rat. Following oral administration to man, the 72-hour urinary excretion was 3–5% of the dose, and fecal excretion was 89–96%. In one of three subjects more than 99% of the dose was excreted within 72 hours, and in the other two the total recovery exceeded 90%. There is no appreciable conversion of SNGA to arsanilic acid, in either man or rat.