Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

The lipid composition and biochemistry of freshwater fish.

For many dietary changes satisfactory prediction of the average change in the serum cholesterol level of man in mg./100 ml., is given by Δ Chol. = 1.35(2ΔS − ΔP) + 1.5ΔZ where S and P are percentages of total calories provided by glycerides of saturated and polyunsaturated fatty acids in the diet and Z2 = mg. of dietary cholesterol/1000 Cal. This formula fails, however, when the dietary change involves large amounts of cocoa butter and discrepancies also appear with beef tallow or hydrogenated coconut oil diets. Controlled dietary experiments at the University of Minnesota and at 2 other centers, provide 63 sets of comparisons of serum cholesterol averages for groups of men on each of 2 chemically characterized diets. Least-squares analysis indicates that stearic acid, as well as saturated fatty acids containing fewer than 12 carbon atoms, have little or no effect on serum cholesterol in man. The equation, Δ Chol. = 1.2(2ΔS′ − ΔP) + 1.5ΔZ, yields good correlation (r = 0.93) with the observed values in these 63 sets of data. This formulation also resolves heretofore puzzling discrepancies in the literature.

Serum cholesterol response to changes in the diet: IV. Particular saturated fatty acids in the diet.

Techniques for the collection of lymph from the liver, small intestine, or thoracic duct of the rat.

Data from 227 men in 10 sets of controlled dietary experiments in 5 institutions gave the least-squares solution: [see text] with S.E. of slope --±0.44, where X is the serum cholesterol level of an individual, X is the average for all men on the same diet, and Δ is the response to a given dietary change. Equations, a chart and a table are provided for the prediction of the serum cholesterol response when change is made from one diet to another when cholesterol and fatty acid compositions of the diets are known. Comparison of predicted with observed average values in recently published data on samples of free-living people changing diets on prescription designed to lower serum cholesterol gave, predicted versus observed Δ: −30.0 vs. −28.5 and −27.2 vs. -30.1 mg./l00 ml. in men and women in caloric balance. In a sample of men who were also losing weight on a low-fat, low-cholesterol diet a change of −33.5 was predicted versus −39.8 observed.

Serum cholesterol response to changes in the diet: III. Differences among individuals.

ECENT studies with C14-labeled palmitic and pentadecanoic acids have shown R that, after their absorption, these fatty acids can be recovered almost quantitatively from intestinal or thoracic duct lymph (I, 2). Since there are indications in the literature that a short-chain fatty acid, such as butyric, does not, to any appreciable extent, make use of lymph (3), we have inquired into the specificity of the lacteal pathway for transport of absorbed fatty acids. The present investigation deals with the extent to which the even-carbon homologues from decanoic to my&tic acids and stearic acid can be recovered in intestinal lymph after their absorption. EXFICRIMENTAL

Intestinal lymph as pathway for transport of absorbed fatty acids of different chain lengths.

Purified alpha-corticotropin has been reported to exercise the following biological effects: (a) stimulation of the adrenal glands in normal and hypophysectomized rats, (b) production of blood eosinopenia in hypophysectomized rats, (c) maintenance of muscle glycogen in hypophysectomized rats, (d) inhibition of growth-promoting activity of somatotropin, (e) stimulation of melanocytes in the skin of frogs, (f) mobilization of fat into the liver of fasted mice, (g) stimulation of the accessory sex glands of castrated-hypophysectomized male rats, (h) induction of deciduoma formation in hypophysectomized-oophorectomized rats, and (i) elevation of the total red cell volume in hypophysectomized rats. alpha-Corticotropin has also been shown for the first time to act in synergism with lactogenic hormone as an essential galactopoietic hormone. The ability of alpha-corticotropin to elicit biological responses in the absence of the adrenal cortex is discussed.

https://rupress.org/jem/article-pdf/105/4/335/1078979/335.pdf

Corticotropins (ACTH). X. Biological investigations on alpha-corticotropin.

SummaryAdministration of purified ACT to the male rat produces by its action on the adrenal cortex a striking reduction in the weight and size of the thymus gland and the cervical lymph nodes. This same effect is not manifest in the adrenalectomized animal. This finding furnishes further evidence for the existence of a definite relationship between adrenal cortex and thymus and lymph nodes. Functional interpretation of this relationship awaits further experimental and clinical study.

Similarity of Response of Thymus and Lymph Nodes to Administration of Adrenocorticotropic Hormone in the Rat.

Summary1. A technic is described for obtaining lymph from the thoracic duct of the rat. 2. The average rate of flow of thoracic duct lymph in the adult, female, unfasted rat, anesthetized with sodium pentobarbital was approximately 0.45 cc/hour (range: 0.13-0.7 in 10 rats). 3. The white cell count of the thoracic duct lymph in 17 rats varied from 6,650-46,250 cells/cu mm and averaged 19,050 cells/cu mm. 4. The rat is a useful and convenient animal to employ in studies on physiology of the lymph.

Rate of Flow and Cell Count of Rat Thoracic Duct Lymph.

THE FRACTION of plasma iodine designated “protein-bound” is the iodine that is precipitated from plasma along with its proteins by such agents as tungstic acid, zinc hydroxide, or acetic acid in the presence of heat and in addition cannot be freed from these proteins by simple washing. Although the chemical identity of this fraction is as yet poorly understood, its concentration in plasma has gained wide use as an indicator of thyroid activity in man. (Salter et al., 1941; Man et al., 1942; Lowenstein et al., 1944; Talbot et al., 1944; Chaney, unpublished observations). In the present investigation, an attempt has been made to determine the metabolic significance of plasma protein-bound iodine. Its concentration in plasma was studied in rats shown to be completely deprived of thyroid tissue and in rats and guinea pigs in which hyperthyroidism had been induced. The use of radioactive iodine (I131) as a labeling agent also made possible a study of the rate of formation of protein-bound iodine in both states...

The metabolic significance of proteinbound iodine of plasma: a study of its concentration under various conditions and of its rate of formation as measured with radioactive iodine

William O. Reinhardt

Papers

Intestinal lymph as pathway for transport of absorbed fatty acids of different chain lengths.

Corticotropins (ACTH). X. Biological investigations on alpha-corticotropin.

Similarity of Response of Thymus and Lymph Nodes to Administration of Adrenocorticotropic Hormone in the Rat.

Rate of Flow and Cell Count of Rat Thoracic Duct Lymph.

The metabolic significance of proteinbound iodine of plasma: a study of its concentration under various conditions and of its rate of formation as measured with radioactive iodine