1. The influence of aliphatic substituents in one or more of positions 4,5 and 6 of the pyrimidine ring of sulfapyrimidines on the solubiity of the free and N 4 -acetyl-substituted compounds in 0.05 M phosphate buffer, pH 6.5, was studied at 37°C. In the majority the acetyl derivative was the more soluble; whatever the relationship, it was often strikingly altered by the addition (or removal) of one or more non-polar groups. In comparison with 4- or 4,6- substituted sulfapyrimidines, 4,5,6- derivatives were nearly always less soluble. If position 4 was occupied, the addition of a methyl group to position 6 usually increased solubility; other compounds of the type 4-R, 6-R9 were more soluble than 4-R compounds, whereas compounds 4-R, 6-R might or might not be more soluble than 4-R compounds. It is believed that the dissociation of a compound as an acid is not the only factor determining solubility. 2. The extent to which the various derivatives of sulfadiazine were bound by human plasma albumin was measured. The introduction of one or more aliphatic radicals in positions 4, 5 or 6 of the pyrimidine ring always led to an increased binding of sulfonamide. Specific aliphatic groups appeared to affect the degree of binding. 3. The absorption and persistence of these sulfonamides were studied in the mouse and monkey to the extent that conclusions can be reached from drug-levels in blood or plasma. The degree of conjugation was also determined in the plasma of monkeys. There were frequent disagreements between the results in mice and those in monkeys. Poor absorption usually was characteristic of drugs of low solubility but could also characterize much more soluble compounds. Specific aliphatic groups and their position appeared to be the principal factors determining absorption, persistence and magnitude of conjugation. The degree of binding to plasma albumin did not alone determine persistence.
SEVERAL RECENT STUDIES from this laboratory offer strong support of the belief (1)that at least two gonadotropins can be isolated from extracts of pituitary glands. Preliminary evidence was obtained from experiments with extracts of hog glands digested by proteolytic enzymes permitting differentiation of gametogenic ('follicle stimulating') and interstitial cell-Stimulating effects depending upon the enzyme used and the extent of digestion (2). Physicochemical methods were next employed to separate the gonadotropins from hog pituitary extracts which had not undergone preliminary enzymic hydrolysis (3). The interstitial cell-Stimulating hormone as a pure protein was isolated (4). The gametogenic hormone was separated as a substance with only one apparent biological effect; however, the purest preparations contained small proportions of two contaminating impurities. Work in the University of California (5) likewise led to the isolation of interstitial cell-Stimulating hormone from pituitary glands of another mammal, the sheep.
1. Urinary excretion measurements indicate considerably lower oral absorption of sulfato-, nitro- and thiocyanato-cobalamin than is exhibited by cyanoeobalamin. In the blood stream, however, the several cobalamins are equivalent in inducing the excretion of ingested vit. B12. 2. That cobalamin urinary excretion responses truly constitute an absorption index was verified in studies comparing chlorocobalamin with cyanocobalamin, by serum level assays in humans and by fecal excretion experiments with rats. 3. Inferior absorption of orally administered nitrocobalamin was confirmed by fecal excretion observations in humans and rats. 4. The superior absorption of cyanocobalamin (vit. B12) over other cobalamins studied is attributed to either the chemical specificity of the substituent cyano group or the tightness of its binding in the cobalt coordination sphere.
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