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The mechanisms by which phosphorus homeostasis is preserved in mammals are not completely understood. We demonstrate the presence of a mechanism by which the intestine detects the presence of increased dietary phosphate and rapidly increases renal phosphate excretion. The mechanism is of physiological relevance because it maintains plasma phosphate concentrations in the normal range after ingestion of a phosphate-containing meal. When inorganic phosphate is infused into the duodenum, there is a rapid increase in the renal fractional excretion of phosphate (FE Pi). The phosphaturic effect of intestinal phosphate is specific for phosphate because administration of sodium chloride does not elicit a similar response. Phosphaturia after intestinal phosphate administration occurs in thyro-parathyroidectomized rats, demonstrating that parathyroid hormone is not essential for this effect. The increase in renal FE Pi in response to the intestinal administration of phosphate occurs without changes in plasma concentrations of phosphate (filtered load), parathyroid hormone, FGF-23, or secreted frizzled related protein-4. Denervation of the kidney does not attenuate phosphaturia elicited after intestinal phosphate administration. Phosphaturia is not elicited when phosphate is instilled in other parts of the gastrointestinal tract such as the stomach. Infusion of homogenates of the duodenal mucosa increases FE Pi, which demonstrates the presence of one or more substances within the intestinal mucosa that directly modulate renal phosphate reabsorption. Our experiments demonstrate the presence of a previously unrecognized phosphate gut-renal axis that rapidly modulates renal phosphate excretion after the intestinal administration of phosphate.

Purpose: The purpose of this study was to develop a new system for computer simulation to predict fraction absorbed (F(a)) of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs after oral administration to humans, from a miniscale dissolution test., Methods: Human oral absorption of 12 lipophilic drugs was simulated theoretically by using the dissolution and permeation parameters of the drugs. A miniscale dissolution test and a solubility study were carried out in a conventional buffer and a biorelevant medium (pH 6.5). A dissolution parameter, which can simulate in vivo dissolution, was obtained from the in vitro dissolution curve. Human intestinal permeability was estimated assuming that the permeation was limited by diffusion through the unstirred water layer. The F(a) in humans was predicted and then compared with clinical data., Results: The dissolution and solubility of most model drugs were faster and higher in a biorelevant medium than in a conventional buffer. The simulated absorption was limited by the drug dissolution rate and/or solubility. Predicted F(a) was significantly correlated with clinical data (correlation coefficient r2 = 0.82, p < 0.001) when the dissolution profiles in biorelevant medium were used for the simulation., Conclusions: This new system quantitatively simulated human absorption and would be beneficial for the prediction of human F(a) values for BCS class II drugs.

The limited contact time of absorbable drug with absorbing surfaces is, in some cases, a significant factor determining the fraction of the dose absorbed. A simple modification of customary linear compartmental models is presented to account for this situation, and a general input function in the Laplace domain for truncated first-order absorption is derived. An extension to series of truncated absorption processes is discussed.

The Loo-Reigelman absorption method provides the correct A infinity/V1 value and the correct rate constant ka (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open models. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A infinity/V1 and ka values are obtained, however, only under conditions not hithertofore specified. Thes conditions are that there must be essentially no bias in the disposition parameters k12, k21 and kel, and in the C0 value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial At/V1, t values frequently provides a better method of estimating A infinity/V1 and ka than the classical method. If biased disposition parameters are used in application of the Loo-Reigelman method oral data, then essentially the correct ovalue of ka will be estimated, but the estimate of A infinity/V1 will be approximately equal to the true value of A infinity/V1 multiplied by the ratio of the biased C0 value (obtained in fitting the intravenous data) to the true C0 value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtainedmthe oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data.

A technique is described for collecting thoracic duct lymph in a portable glass saddle from an unrestrained rat. Uniformly labelled oleic acid in various physical states was given to rats with thoracic duct and bile fistulae to study the influence of bile salts on the amount absorbed and on the route of transport and esterification after absorption. It is suggested that in addition to their emulsifying action bile salts may stimulate the esterification of absorbed oleic acid by the intestinal mucosa.

The absorption of water, sodium, and potassium from isolated segments of the large intestine has been studied in 11 patients. In eight control segments adjacent to a carcinoma of the colon, absorption of water and sodium and secretion of potassium occurred. In five segments of intestine containing a villous papilloma, water, sodium, and potassium were secreted. The difference is mainly due to an increase in exsorption of sodium and water, insorption being relatively unaffected.

A method is reported that enables selective suppression of absorption of radioactive strontium from ingested food material, permitting calcium to remain available to the body. Studies were carried out by measuring blood levels and bone uptake of Sr(89) and Ca(45) at different time intervals after orogastric intubation of rats. The addition of sodium alginate, derived from brown marine algae, to the radioactive isotopes increased the overall physiological discrimination against strontium by amounts up to 60% after 24 hours. This discrimination was further increased by feeding sodium alginate mixed with standard diet in the proportions of 20:80 and 30:70. The observed ratio was reduced by administration of sodium alginate from 0.25 to 0.09.Determination of the limiting dosage in rats is restricted to the amounts which rats will consume. In the event of an inadvertent release of radioactive strontium, human subjects probably could increase their intake of alginate at will, permitting a greater effectiveness of sodium alginate than could be obtained in experimental animals.

A method is reported which permits selective suppression of absorption of radioactive strontium from ingested food material, permitting the calcium to be available to the body. Studies were carried out in vivo by injection of Sr(89) and Ca(45) in the presence of inert carrier into ligated intestinal segments in rats, and the amount of absorption was measured by standard monitoring techniques. The pattern of absorption of both ions is very similar but the rate of absorption is different. It was found that the polyelectrolyte, sodium alginate, obtained from brown algae (Phaeophyceae), injected simultaneously with radiostrontium effectively reduces the absortion of Sr(89) from all segments of the intestine by as much as 50-80% of the control values. No significant reduction in absorption of Ca(45) was observed in equivalent concentrations. The reduction in blood levels of Sr(89) and in bone uptake corresponded to the absorption pattern. The difference in the effect on strontium and calcium absorption may be due to differences in the binding capacity of sodium alginate from the two metal ions under the conditions present in vivo.