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Effective intestinal absorption of insulin in diabetic rats using a new formulation approach.

Insulin injected intra-jejunally together with the non-ionic surfactant cetomacrogol was effective in streptozocin-induced diabetes in the rat, as measured by the hypoglycaemic effect. The reduction in blood sugar was maximal at about 2 h after administration but continued at a high level for the 4 h of the experiment. No hypoglycaemic effect was observed in controls injected with insulin or saline alone. Intestinal absorption of insulin has thus been effected by the addition of cetomacrogol, which appears to enhance membrane-permeability to insulin rather than to function as a protective agent preventing insulin degradation, as in liposome-encapsulation. In support of this, a significant hypoglycaemic action was still obtained when the insulin injection was given half-hour after that of the cetomacrogol, both intra-jejunally. Furthermore, oral administration of the surfactant followed by intra-jejunal injection of the insulin also gave a hypoglycaemic effect. The use of this agent to enhance insulin absorption offers the possibility of a new approach to oral insulin therapy.

Animals↗

Familial iminoglycinuria with normal intestinal absorption of glycine and imino acids in association with profound mental retardation, a possible "cerebral phenotype".

Spasticity and severe psychomotor retardation in a 2-year-old girl, apparently in expression of chronic progressive encephalopathy, was found in association with prolinuria, hydroxyprolinuria and hyperglycinuria. The pattern and levels of these amino acids in plasma proved to be normal, however, as was their intestinal absorption as well as their concentration in cerebrospinal fluid. The proband appears to be homozygous for iminoglycinuria with an apparent inborn defect of the renal tubular transport system specific to these amino acids. An isolated hyperglycinuria, however, was traced in several obligate heterozygotes in this family. The possibility of a more direct causative link between this anomaly and her clinical manifestations is discussed. Where instances of iminoglycinuria occur in association with cerebral pathology of this type, an analogous impairment of a correspondingly specific cerebral amino acid transport system is postulated.

Amino Acid Metabolism, Inborn Errors↗

An experimental assessment of the Wagner-Sedman extraction theory for the intestinal absorption of antibacterial sulfonamides.

The chromatographic parameters in a reverse-phase partition system and the rat gut in situ absorption rate constants for 18 antibacterial sulfonamides are highly correlated values. The correlation is logarithmic-logistic in nature, being in accordance with the Wagner-Sedman extraction theory for a constant pH value. Parabolic correlations did not satisfactorily fit the experimental data. This behavior, not frequently reported in regard to the intestinal absorption of drugs, is discussed in connection with other apparently contradictory available data.

Animals↗

The effect of elevated prolactin levels on plasma 1,25-dihydroxyvitamin D and intestinal absorption of calcium.

Because of evidence in experimental animals that prolactin stimulates production of 1,25-dihydroxyvitamin D, we evaluated several indices of calcium metabolism in patients who had hyperprolactinemia due to functioning pituitary adenomas and in normal age-matched controls. Plasma levels of 1,25-dihydroxyvitamin D in hyperprolactinemic patients were in the normal range (15 to 24 pg/ml versus 15 5o 75 pg/ml in controls). Intestinal absorption of calcium, plasma levels of immunoreactive parathyroid hormone, and serum values for calcium, phosphorus, and alkaline phosphatase were similar in patients and controls. We conclude that prolactin probably has no effect on plasma 1,25-dihydroxyvitamin D levels or calcium metabolism in man.

Adenoma↗

The age-dependence of intestinal absorption using d-xylose as an example.

In 40 infants the serum concentrations of D-xylose were measured from capillary blood samples up to 300 min after an oral dosage of 0.5 g of D-xylose per kg body weight. The parameters of the absorption kinetics, which are calculated by a digital computer program, showed an age-dependent behavior. Infants up to the age of 2 months have lower maximal serum concentrations compared to older ones because of a larger volume of distribution. The rate constant of invasion k1, which serves as a measure for the rate of intestinal absorption and the rate constant of elimination k2 were significantly lower in infants up to the age of 2 months compared to older ones. The quotient of k1:k2 was independent of age. The time it took to reach maximal serum concentration was significantly longer in young infants. By adding metoclopramide simultanously to the oral D-xylose doses it could be demonstrated that the slower motility of the gastrointestinal tract in newborns and young infants is not exclusively responsible for the slower rate of absorption of D-xylose. Comparing the absorption rates in 26 infants after different D-xylose dosages a saturation kinetics may be supposed.

Age Factors↗

Intestinal absorption of water-soluble vitamins: an update.

PURPOSE OF REVIEW: The molecular biology revolution has led to a significant improvement in our understanding of biological and physiological processes. Such expansion of knowledge has also covered the field of intestinal absorption of water-soluble vitamins and is the subject of this review. RECENT FINDINGS: Impressive progress has been made in the understanding of the mechanisms and regulation of transport of water-soluble vitamins at the cellular and molecular levels. In addition, the 5' regulatory regions of the genes that encode a number of the involved transporters have been cloned and characterized in vitro and in vivo in transgenic mice, thus providing important information about transcriptional regulation of these events. Furthermore, confocal imaging of live intestinal epithelial cells has led to significant progress in understanding the mechanisms involved in intracellular trafficking and membrane targeting of the carrier proteins and how clinical mutations lead to interference with transport. Finally, the identification in the large intestine of efficient and specialized carrier-mediated systems that are capable of absorbing a number of the bacterially synthesized vitamins (thiamin, folate, biotin, riboflavin, pantothenic acid) has raised the possibility that this source of vitamins may play a role in regulating (fine tuning) the normal body homeostasis of these vitamins, and especially the vitamin level in the local colonocytes. SUMMARY: Water-soluble vitamin absorption involves regulated and specific mechanisms. Interference with the function of these mechanisms may lead to deficiency. The large intestine is capable of absorbing water-soluble vitamins that are synthesized by the normal microflora.

Animals↗

Effects of leucine supplemented diet on intestinal absorption in tumor bearing pregnant rats.

BACKGROUND: It is known that amino acid oxidation is increased in tumor-bearing rat muscles and that leucine is an important ketogenic amino acid that provides energy to the skeletal muscle. METHODS: To evaluate the effects of a leucine supplemented diet on the intestinal absorption alterations produced by Walker 256, growing pregnant rats were distributed into six groups. Three pregnant groups received a normal protein diet (18% protein): pregnant (N), tumor-bearing (WN), pair-fed rats (Np). Three other pregnant groups were fed a diet supplemented with 3% leucine (15% protein plus 3% leucine): leucine (L), tumor-bearing (WL) and pair-fed with leucine (Lp). Non pregnant rats (C), which received a normal protein diet, were used as a control group. After 20 days, the animals were submitted to intestinal perfusion to measure leucine, methionine and glucose absorption. RESULTS: Tumor-bearing pregnant rats showed impairment in food intake, body weight gain and muscle protein content, which were less accentuated in WL than in WN rats. These metabolic changes led to reduction in both fetal and tumor development. Leucine absorption slightly increased in WN group. In spite of having a significant decrease in leucine and methionine absorption compared to L, the WL group has shown a higher absorption rate of methionine than WN group, probably due to the ingestion of the leucine supplemented diet inducing this amino acid uptake. Glucose absorption was reduced in both tumor-bearing groups. CONCLUSIONS: Leucine supplementation during pregnancy in tumor-bearing rats promoted high leucine absorption, increasing the availability of the amino acid for neoplasic cells and, mainly, for fetus and host utilization. This may have contributed to the better preservation of body weight gain, food intake and muscle protein observed in the supplemented rats in relation to the non-supplemented ones.

Animals↗

Interleukin-11 enhances intestinal absorptive function after ischemia-reperfusion injury.

BACKGROUND/PURPOSE: Interleukin-11 (IL-11) is a multifunctional cytokine that has been shown to improve small bowel adaptation and enhance cellular recovery after bowel ischemia. This study was designed to examine the effects of systemic IL-11 on small bowel absorptive function in a rat model of intestinal ischemia and reperfusion (IR) injury. METHODS: Sprague-Dawley rats underwent placement of a venous catheter connected to an osmotic pump, which delivered its contents over 3 days. Rats were divided into 3 groups: sham operation/systemic saline; 30-minute superior mesenteric artery occlusion/systemic saline; superior mesenteric artery occlusion/systemic IL-11, 750 microgram/kg/d. After the infusion, (14)C-galactose or (14)C-glycine absorption was measured using an in vivo, recirculation technique. Statistical significance was determined using analysis of variance. RESULTS: In control rats, 30 minutes of IR decreased absorption of galactose from 2.62 to 2.02 micromoles/cm(2) (P <.01), and glycine from 2.79 to 1.72 micromoles/cm(2) (P <.01). Rats treated with systemic IL-11 showed improved absorption of galactose of 2.39 micromoles/cm(2) (P <.05), and glycine at 2.21 micromoles/cm(2) (P <.05). Mucosal DNA content was reduced significantly from 7.37 to 5.61 microgram DNA/mg by IR (P <.01). IL-11 treatment did not significantly alter DNA content during this period. CONCLUSIONS: These data show that 30 minutes of intestinal IR significantly decreases intestinal absorptive function in this animal model. When compared with untreated control animals, administration of systemic IL-11 significantly increased the absorption of carbohydrate and amino acid in rats recovering from mesenteric IR.

Animals↗

Intestinal absorption and retention of cadmium in neonatal pigs compared to rats and guinea pigs.

The purpose of this study was to measure intestinal absorption and retention of cadmium in the newborn pig and to compare data from the pig, rat and guinea pig, three species that differ greatly in their ability to absorb macromolecules at birth. Newborn pigs were administered a single oral dose of 50 muCi of 115mCd (0.20 mCi/mg Cd) 24 hours after birth and killed at intervals between 1 and 14 days after dosing. Cd absorption and gastrointestinal retention were then determined; these data were compared with similar data from the rat and guinea pig. The cumulative Cd absorption was about 4.0, 5.0 amd 23% of the dose in the day-old pig, rat and guinea pig, respectively. The residence time of Cd in the intestinal tract was longer in the rat than in the pig or guinea pig, the 50% excretrion time being 15, 8, and 5 days in the rat, pig and guinea pig, respectively. Cd absorption in the neonate appears to be a two-step process: mucosal uptake of Cd from the lumen, probably by pinocytosis, followed by transfer of a portion of this Cd into the body. This transfer process is similar, but does not entirely coincide with changes associated with protein absorption in the neonate.

Age Factors↗

Prediction of intestinal absorption and blood-brain barrier penetration by computational methods.

This review surveys the computational methods that have been developed with the aim of identifying drug candidates likely to fail later on the road to market. The specifications for such computational methods are outlined, including factors such as speed, interpretability, robustness and accuracy. Then, computational filters aimed at predicting "drug-likeness" in a general sense are discussed before methods for the prediction of more specific properties--intestinal absorption and blood-brain barrier penetration--are reviewed. Directions for future research are discussed and, in concluding, the impact of these methods on the drug discovery process, both now and in the future, is briefly considered.

Animals↗

Intestinal absorption of rutin in free and conjugated forms.

Quercetin is one of the most common flavonoids in nature, occurring mainly in glycosidic forms such as rutin. Rutin has been reported to exert numerous biochemical and pharmacological activities, though information about its absorption and metabolism is scarce. The aim of this study was to investigate intestinal handling of luminally administered rutin in an isolated preparation of luminally and vascularly perfused rat small intestine. A synthetic perfusate free from blood components was used as vascular medium, with a perfluorocarbon as oxygen carrier. Luminal media consisted of a bicarbonate-buffered sodium chloride solution spiked with rutin (40.5 +/- 1.8 micromol/L). Viability was maintained during the entire perfusion; no differences between rutin and control perfusions for perfusion pressure, lactate-pyruvate ratio, oxygen uptake, and acid-base homeostasis were observed. About 10% of the administered rutin appeared at the vascular side, chiefly as free rutin (5.6%), but some rutin sulfate (2.5%) and glucuronide (2.0%) were also detected. The conjugates were preferentially absorbed to the vascular side, while only traces of the glucuronide (0.2%) were found in the luminal perfusate. Minute amounts of the rutin administered were located in the intestinal tissue (1.1%) in the form of unchanged rutin and its glucuronide and sulfate conjugates. The model used serves as a valuable tool for understanding intestinal handling of the bioactive flavonol glycoside rutin, and the obtained results confirm uptake of rutin in the rat small intestine.

Animals↗

Roles of molecular chaperones in pancreatic secretion and their involvement in intestinal absorption.

This review focuses on the contribution of molecular chaperones in the secretory process of digestive enzymes and their interaction with enterocytes. By using biochemistry and immunocytochemistry, we have shown that Grp94, Cpn10, Cpn60, and protein disulfide isomerase (PDI) are present all along the rough endoplasmic reticulum-Golgi-granule secretory pathway of the pancreatic acinar cells and are secreted into the acinar lumen. Two other molecular chaperones, Grp78 and the Hsp70, appear to be restricted to the rough endoplasmic reticulum and the trans-Golgi apparatus, respectively. We have found that chaperones can be associated with pancreatic enzymes along the secretory pathway. Indeed, double immunogold and immunocoprecipitation revealed an association between Cpn60 and the colipase-dependent lipase (CDL) and between Grp94 and the bile salt-dependent lipase (BSDL). These complexes are secreted into the acinar lumen and diverted to the duodenal lumen. These findings led us to investigate these enzyme-chaperone complexes in intestinal tissue. Grp94, Cpn60, and PDI are present on microvilli and on the endosomal compartment of enterocytes. Furthermore, we have shown that the Grp94-BSDL complexes are internalized by enterocytes through classical endocytosis. Upon dissociation of the BSDL-Grp94 complex in the late endosome, BSDL is transferred to the basolateral membrane. We propose that Grp94 interacts with specific receptors and/or could force the associated protein to adopt a specific conformation that allows its binding to corresponding membrane receptors and its internalization by enterocytes. These two hypotheses need not to be exclusive. The existence of such a pancreatic secretion-intestinal absorption link speaks in favor of a coordinated functional connection between these two entities, through molecular chaperones, in order to optimize intestinal activities.

Animals↗

Intestinal absorption of fish oil in rats previously adapted to diets containing fish oil or corn oil.

A study was conducted to evaluate whether the composition of previous dietary fat affects the absorption and composition of lymph obtained after a meal of fish oil. Adult male Sprague-Dawley rats were fed diets containing either corn oil or fish oil (MaxEPA) for 2 weeks. They were then given intraduodenally a bolus of an emulsion of 0.5 ml of fish oil plus 0.5 ml of 20 mM sodium taurocholate. Intestinal lymph was collected from a cannula in the main intestinal lymph trunk for various times after oil administration. Rats proportion of the test dose fo fish oil than those fed corn oil. There was an effect of previous diet on the fatty acid composition of the lymph. Rats fed fish oil had a higher percentage of eicosapentaenoic and docosahexaenoic acids in the lymph lipids than those fed corn oil while those fed corn oil had a higher percentage of linoleic acid. These results rule out decreased intestinal absorption as a mechanism for the hypotriacylglycerolemic effect of dietary fish oils. They also indicate a significant contribution of endogenous lipids to the fatty acids in lymph.

Adaptation, Physiological↗

Decreased intestinal absorption of methotrexate in the rat following repeated oral dosing.

The absorption of methotrexate (MTX) following single and repeated oral administrations was investigated in the rat and compared with that after intravenous injections. The absorption of intermediate dose MTX was poor (14.7%), both after single gift (25 mg X kg-1) and when given repeatedly at 72-hour intervals (3 X 25 mg X kg-1). Repeated oral administration did not produce higher plasma concentrations of MTX in spite of decreased elimination as a result of impaired renal clearance. It is concluded from these experiments that repeated oral administration of MTX when spaced 72 hours apart leads to a deterioration of the already incomplete intestinal absorption of the drug in the rat.

Administration, Oral↗

Physiology and pathophysiology of intestinal absorption.

Final digestion and absorption of carbohydrates (CHO) occur after intraluminal hydrolysis by pancreatic alpha-amylase at the surface of the mucosal membrane in close relationship between disaccharide hydrolysis and the glucalogue carrier system. In general, Na(+)-dependent transport is the rate-limiting step of CHO absorption. The rate of absorption is determined by mode of ingestion, chemical composition of the meal, gastric emptying, pancreatic digestion, intestinal digestion and absorption, and intestinal motility. A delay of absorption of CHO may be achieved by dietary fibers, alpha-amylase inhibitors, or alpha-glucosidase inhibitors. Final protein digestion is achieved by a dual mechanism: intact peptide absorption with subsequent intracellular hydrolysis to free amino acids (AA) and membrane hydrolysis of peptides followed by absorption of free AA. More complex is the mechanism of lipid absorption: emulsification, lipolysis, micellar formation, membrane translocation, intracellular resynthesis, chylomicron formation, and lymphatic drainage. The most critical steps in lipid digestion are lipolysis and micellar formation.

Dietary Carbohydrates↗

Fetal rabbit intestinal absorption: implications for transamniotic fetal feeding.

Delivery of nutrients to the fetus via the developing gastrointestinal tract has been advocated as a potential prenatal treatment for intrauterine growth retardation. Previous studies have demonstrated significant increases in fetal length and weight following continuous intraamniotic nutrient infusions in animals. The ideal composition of intraamniotic feedings has yet to be determined. Thirteen time-mated rabbit does underwent ceserean section between gestational days 27 and 33 to deliver 54 fetuses. The everted intestinal sleeve technique was used to measure radiolabeled carbohydrate and amino acid uptake rates from 1-cm segments of midjejunum. Uptake of galactose was more than double that of glucose and fructose. Active uptake of glucose, fructose, and galactose increased by 3.3-fold, 6.2-fold, and 2.1-fold, respectively, during the final 7 days of gestation when expressed as uptake per mg intestine. In contrast, uptake of the amino acids leucine, lysine, and proline decreased by 41%, 34%, and 17%, respectively, during the final 5 days of gestation. The demonstrated changes in intestinal absorption and nutrient delivery in the rabbit model, during the last days of gestation, suggest that certain substrates are absorbed more rapidly than others. Galactose may be the preferred intraamniotic carbohydrate for fetal growth.

Amino Acids↗