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PubMed1969

Effect of bile acids on the intestinal absorption of endotoxin in rats.

The absorption of tritium-labeled Escherichia coli O89 Westphal-type endotoxin from the peritoneal cavity of rats was diminished by bile by 23% and by sodium deoxycholate by 47%, respectively. Practically, there is no endotoxin absorption from the intestinal tract of normal rats. The bile duct of rats was chronically cannulated for experimental purposes. A significant amount of perorally administered endotoxin absorbed from the intestinal canal into the blood in the rats treated thus. Absorption was demonstrated by the lethal effect of endotoxin on rats previously hypersensitized by lead acetate, and by the radioactivities found in the blood samples. The intestinal absorption of endotoxin in rats, rendered bile-deficient, may be prevented by sodium deoxycholate. Supported by their experimental findings, we emphasize the important role of bile acids in the defense mechanism of the macroorganism against bacterial endotoxins.

Animals↗
PubMed1975

Effects of dietary lactose and lactase preparation on the intestinal absorption of calcium and magnesium in normal infants.

Effects of dietary lactose and a lactase preparation on the intestinal absorption of calcium and magnesium were studied in 3 groups under 8 months of age; infants on a proprietary milk, infants on a lactose-free milk, and infants on a proprietary milk to which a lactase preparation was added. The intestinal absorption of both elements was reduced in infants on a lactose-free milk and enhanced in infants who were fed on a proprietary milk and given a lactase preparation.

Animals↗
PubMed2002

Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats.

The intestinal absorption of cadmium (Cd) increases when the body iron (Fe) stores are depleted. The depletion of Fe upregulates the expression of divalent metal transporter 1 (DMT1), which is located at the apical membrane of enterocytes lining the small intestine. DMT1 has been shown to transport Fe and other divalent metal ions in vitro. However, it is not known whether DMT1 mediates the intestinal absorption of Cd. To investigate DMT1 involvement in Cd absorption, rats were fed a diet for 4 weeks either deficient in Fe (FeD diet, 2-6 mg Fe/kg) or supplemented with Fe (FeS diet, 120 mg Fe/kg), followed by a single oral administration of 109 CdCl2. Body Fe status, hemoglobin, and tissue Cd concentration were determined at 48 h after Cd administration. Also, DMT1 mRNA levels were quantified in duodenum, kidney, and liver by the branched DNA signal amplification method. Animals fed the FeD diet exhibited a reduced body weight gain, depletion of body Fe, and Fe deficiency anemia. Tissue Cd concentration was significantly higher in FeD than in FeS diet-fed rats, especially in the duodenum. The amount of Cd retained in the body was 10-fold higher in rats fed the FeD diet than in those fed the FeS diet. DMT1 mRNA was highly expressed in duodenum and was 15-fold higher in the FeD diet group. The levels of DMT1 mRNA were significantly lower in kidney and liver than in duodenum, but were 30 and 40% higher, respectively, in rats fed the FeD diet than in rats fed the FeS diet. These findings suggest that functional DMT1 protein is likely upregulated in the small intestine at the mRNA level by body iron depletion and increases Cd uptake from the gastrointestinal tract with subsequent transfer of Cd to the circulation and body tissues. Furthermore, the data from this study may indicate that DMT1 is a nonspecific metal transporter, which can transport not only Fe, but probably the toxic metal as well.

Anemia, Iron-Deficiency↗
PubMed1980

Binding of cationized ferritin to the cell-coat glycoproteins of human and rat small-intestinal absorptive cells.

The binding of cationized ferritin (CF) to the cell-coat (glycocalyx) glycoproteins of human and rat intestinal absorptive cells was investigated in relation to the amount of sialic acid in these macromolecules. The cell coat of human absorptive cells exhibited poor binding of CF and contained a small amount of sialic acid. The cell coat of rat absorptive cells had about ten times more sialic acid than that of human cells and showed a strong affinity for the marker. The removal of sialic acid from the cell-coat glycoproteins of rat intestinal cells by neuraminidase treatment abolished CF binding. These results suggest that sialic acid is necessary for CF binding and that human and rat intestinal absorptive cells show a species-specific difference in the sugar composition of the cell coat.

Animals↗
PubMed1979

Intestinal absorption and lymphatic transport of cholesterol and beta-sitostanol in the rat.

The intestinal absorption of cholesterol and beta-sitostanol (the saturated analogue of beta-sitosterol) were measured and their absorptions compared in the presence and absence of cholestyramine. After test meals containing [(3)H]cholesterol and [(14)C]beta-sitostanol without added cholestyramine, 4-day fecal collections yielded an average of 51% of the fed cholesterol and 83% of the fed beta-sitostanol. In separate lymph transport studies without cholestyramine, 36% of the fed cholesterol was recovered in lymph in 24 hours compared to only 2% of the fed beta-sitostanol. Thus, while total recoveries of the two labeled compounds in feces plus lymph were nearly identical (51% + 36% = 87% for cholesterol and 83% + 2% = 85% for beta-sitostanol) their distribution in the two compartments was markedly different, reflecting the relative nonabsorbability of beta-sitostanol. Adding cholestyramine to the test meal caused fecal excretion of cholesterol to increase to 73%, independent of the dose of cholestyramine used. Cholestyramine had no effect on the fecal excretion of beta-sitostanol (average excretion after cholestyramine, 85%). The relative non-absorbability of beta-sitostanol compared to cholesterol is clearly evident in this study and leads us to suggest its possible use as a lipid-soluble, nonabsorbable reference compound for measurement of the absorption of cholesterol and other lipids. Further data are presented to justify its use for this purpose.-Hassan, A. S., and A. J. Rampone. Intestinal absorption and lymphatic transport of cholesterol and beta-sitostanol in the rat.

Animals↗
PubMed2002

ADME evaluation. 2. A computer model for the prediction of intestinal absorption in humans.

PURPOSE: To develop a computational method to rapidly evaluate human intestinal absorption, one of the drug properties included in the term ADME (Absorption, Distribution, Metabolism, Excretion). Poor ADME properties are the most important reason for drug failure in clinical development. METHODS: The model developed is based on a modified contribution group method in which the basic parameters are structural descriptors identified by the CASE program, together with the number of hydrogen bond donors. RESULTS: The human intestinal absorption model is a quantitative structure-activity relationship (QSAR) that includes 37 structural descriptors derived from the chemical structures of a data set containing 417 drugs. The model was able to predict the percentage of drug absorbed from the gastrointestinal tract with an r2 of 0.79 and a standard deviation of 12.32% of the compounds from the training set. The standard deviation for an external test set (50 drugs) was 12.34%. CONCLUSIONS: The availability of reliable and fast models like the one we propose here to predict ADME/Tox properties could help speed up the process of finding compounds with improved properties, ultimately making the entire drug discovery process shorter and more cost efficient.

Adsorption↗
PubMed1989

Intestinal absorption of stearic acid after consumption of high fat meals in humans.

The intestinal absorption of stearic acid (18:0), relative to other fatty acids, was evaluated in a group of 10 normal volunteers. Subjects were fed two types of high fat meals; one contained a relatively high content of stearic acid and the other a relatively low content. Plasma chylomicrons were isolated at 2, 4, 6 and 8 h after ingestion of the meals. Fatty acid patterns of chylomicron lipids were determined, and relative intestinal absorption rates of each fatty acid were estimated by comparing the fatty acid composition of chylomicron lipids with that of the fat in the meals. Overall, for both meals the fatty acid pattern of chylomicron lipids was very similar to that of ingested fat. Percentages of palmitic acid (16:0) and stearic acid, relative to other fatty acids, were only slightly lower in chylomicron lipids than in the meal fat. These data suggest that intestinal absorbability of stearic acid is similar to that of palmitic acid, and both saturated fatty acids appear to be absorbed almost as well as oleic acid (16:1).

Adult↗
PubMed2006

Methylated flavonoids have greatly improved intestinal absorption and metabolic stability.

To better understand the relationship between the chemical structure and biological fate of dietary polyphenols, the hepatic metabolic stability and intestinal absorption of methylated polyphenols, in comparison with unmethylated polyphenols, were investigated in pooled human liver S9 fraction and human colon adenocarcinoma (Caco-2) cells. Consistent with previous in vivo studies, the two well known unmethylated polyphenols resveratrol (3,5,4'-trihydroxystilbene) and quercetin (3,5,7,3',4'-pentahydroxyflavone) were rapidly eliminated by the S9 fraction in the presence of the appropriate cofactors for conjugation and oxidation. In contrast, the methylated flavones, i.e., 7-methoxyflavone, 7,4'-dimethoxyflavone, 5,7-dimethoxyflavone, and 5,7,4'-trimethoxyflavone, were relatively stable, indicating high resistance to hepatic metabolism. The corresponding unmethylated flavones, i.e., 7-hydroxyflavone, 7,4'-dihydroxyflavone, chrysin (5,7-dihydroxyflavone), and apigenin (5,7,4'-trihydroxyflavone), were rapidly eliminated because of extensive glucuronidation and/or sulfation just as resveratrol and quercetin were. The rate of intestinal absorption was evaluated using Caco-2 cells grown in porous inserts. The methylated flavones showed approximately 5- to 8-fold higher apparent permeability (P(app), 22.6-27.6 x 10(-6) cm s(-1)) of apical to basolateral flux than the unmethylated flavones (P(app), 3.0-7.8 x 10(-6) cm s(-1)). The lower P(app) values for the unmethylated flavones correlated with their extensive metabolism in the Caco-2 cells. Thus, combined use of the hepatic S9 fraction and Caco-2 cells will be useful for predicting the oral bioavailability of dietary polyphenols. The higher hepatic metabolic stability and intestinal absorption of the methylated polyphenols make them more favorable than the unmethylated polyphenols to be developed as potential cancer chemopreventive agents.

Biological Transport↗
PubMed2006

Intestinal absorption characteristics of ketoprofen in rats.

The present study aims to investigate the intestinal absorption characteristics of ketoprofen in rats. The pharmacokinetic profile of ketoprofen was evaluated following a single p.o. administration of ketoprofen (1 mg/kg) to rats in the absence and presence of benzoic acid or lactic acid (2 and 10 mg/kg), the substrates of monocarboxylic acid transporters. The pharmacokinetic profiles of ketoprofen (1 mg/kg) were significantly altered by the concurrent use of benzoic acid or lactic acid (10 mg/kg), compared with the control (given ketoprofen alone). The Cmax and AUC of ketoprofen in the presence of benzoic acid or lactic acid (10 mg/kg) were significantly (p<0.05) lower than those from the control group, while there was no significant change in Tmax and the terminal plasma half-life (T1/2) of ketoprofen. These results suggest that ketoprofen shares a common transport pathway with benzoic acid and lactic acid during the intestinal absorption in rats.

Animals↗
PubMed1991

The effect of exercise associated with subchronic poisoning with potassium nitrate and sodium nitrite on the processes of intestinal absorption of D-xylose in rats.

The intestinal absorption of D-xylose was studied during the subchronic poisoning of male Wistar rats with orally administered potassium nitrate and sodium nitrite associated with exercise; running on a moving track during the last two weeks of poisoning. The metabolic parameters of Na+/K(+)-ATPase, alkaline phosphatase, oxygen uptake, and lactic acid level in the small intestine mucosa were determined one hour after D-xylose treatment. Exercise increased the toxicity of potassium nitrate and sodium nitrite. The experiment demonstrated post-exercise reduction of D-xylose absorption and decrease activity of Na+/K(+)-ATPase and alkaline phosphatase. Exercise caused transient hypoxia of the small intestine, which was observed only in the groups subjected to exercise on the day of the determinations.

Administration, Oral↗
PubMed1994

Intestinal absorption of vitamin A in streptozotocin-induced diabetic rats.

Diabetes mellitus is known to be associated with enhanced intestinal absorption of lipids. A validated in vitro technique was used to examine the uptake of (3H) retinol (a lipid soluble vitamin) into the jejunum and ileum of streptozotocin (STZ)-induced diabetic rats. In addition, availability of vitamin A in the plasma and liver of diabetics which were pair-fed to non-diabetic control rats was investigated. The relationship between the duration of incubation and retinol uptake was curvilinear in both the jejunum and the ileum, but no difference in intestinal uptake was observed between the two groups of animals. A linear relationship was noted between the concentration of retinol and uptake into both the jejunum and ileum. There was no difference in the uptake of retinol between the diabetic and control animals. The hepatic concentration of vitamin A also remained unaffected by diabetes as indicated by similar values found between pair-fed diabetic and non-diabetic control rats. Unlike the liver, plasma retinol level was decreased in the diabetic animals; this effect does not appear to be caused by any change in the intestinal absorption of the vitamin.

Animals↗
PubMed1995

Biodiscrimination of alpha-tocopherol stereoisomers during intestinal absorption.

Synthetic alpha-tocopherol (alpha-Toc) contains equal amounts of eight different stereoisomers, and the four stereoisomers with the 2R configuration are generally more active than their corresponding 2S-isomers. We investigated the biodiscrimination of alpha-Toc stereoisomers during intestinal absorption in situ and in vitro. Intestinal absorption of alpha-Toc stereoisomers was examined in situ in vitamin E-deficient rats with cannulated thoracic ducts. We found that the ratios of alpha-Toc stereoisomers in lymph of the all-rac-alpha-Toc group were the same as the administered alpha-Toc stereoisomers, and 2R-isomers occupied approximately 50% of absorbed alpha-Toc. The uptake of alpha-Toc stereoisomers also was measured using Caco-2 cells cultured on filter membranes. The concentration of RRR-alpha-Toc in Caco-2 cells was not significantly different from that of SRR-alpha-Toc. Therefore, the discrimination of alpha-Toc stereoisomers does not occur during absorption in small intestine, suggesting the liver as source for the biodiscrimination.

Animals↗
PubMed1999

Intestinal absorption of calcium from calcium ascorbate in rats.

The intestinal absorption of calcium (Ca) from Ca ascorbate (Ca-AsA) was investigated in normal rats. Each animal was perorally administered either 5mg (low dose) or 10mg (high dose) of Ca in 1ml of distilled water as Ca-AsA, Ca carbonate (CaCO3), or Ca chloride (CaCl2), which were intrinsically labeled with 45Ca using 45CaCl2. The amount of radioactivity in plasma was measured periodically up to 34h after dosing, and pharmacokinetic parameters were calculated from the radioactivity in plasma. The time taken to reach the maximum 45Ca level (Tmax) did not differ among the three groups. The area under the plasma 45Ca level/time curve (AUCinfinity) value for the Ca-AsA group was significantly higher than those for the CaCO3 and the CaCl2 groups. The radioactivity at Tmax (Cmax) for the Ca-AsA group was significantly higher than those for the CaCO3 and the CaCl2 groups for the low dose, and comparable with or significantly higher than those for the CaCl2 and CaCO3 groups for the high dose. Similar results were observed for whole-body 45Ca retention. Radioactivity in the femur 34h after dosing was the highest in the Ca-AsA group and the lowest in the CaCO3 group. The rank order of solubility in water, the first fluid (pH 1.2, JP-1) of JPXIII disintegration medium, acetate buffer solution (pH 4.0), triethanolamine-malate buffer solution (pH 7.0) and ammonium chloride buffer solution (pH 10.0) at 37 degrees C was CaCl2 > Ca-AsA > CaCO3. In contrast, the rank order of the solubility in the second fluid (pH 6.8, JP-2) of JPXIII disintegration medium at 37 degrees C was Ca-AsA > CaCl2 > CaCO3. These results indicate that the absorbability of Ca from Ca-AsA is almost comparable with, or higher than, that from CaCl2 and significantly higher than that from CaCO3 because of its high degree of solubility in the intestine. Therefore, Ca-AsA would be useful as a Ca supplement with relatively high absorption from intestine.

Animals↗
PubMedDate not supplied

Intestinal absorption of thiamine, glucose and sodium in rats after lead and joint lead-zinc treatment.

Intestinal absorption of thiamine, glucose and sodium was studied by perfusion method in situ in control rats, in rats subchronically poisoned with lead and in rats subchronically poisoned with lead and zinc administered jointly. In lead poisoned rats absorption of the investigated substances was increased. In lead and zinc poisoned rats intestinal absorption was not elevated. This seems to indicate that interaction between lead and zinc was antagonistic also when the metals were administered parenterally.

Animals↗
PubMed1985

In vivo intestinal absorption of selenate and selenite by rats.

Intestinal absorption of selenate and selenite was investigated in rats by using an in vivo perfusion technique. Different segments of the intestine were perfused with an isotonic solution containing different concentrations of SeO42- or SeO32-. The site of greatest SeO42- absorption was found to be the ileum followed in descending order by the proximal jejunum and large intestine (cecum and colon). Furthermore, SeO42- was absorbed significantly faster from the ileum than SeO32-. The concentration dependence of SeO42- absorption indicates that SeO42- is absorbed by a saturable transport mechanism of the ileal mucosa. Absorption of SeO42- at a concentration of 0.01 mM was not affected by the presence of 1 mM SeO42- in the perfusate. When the SeO42- concentration of the perfusate was increased to 1 mM, the absorptive functions of the ileal epithelium appeared to be generally impaired. It is concluded that selenate is absorbed from the ileum by a carrier-mediated mechanism.

Animals↗
PubMed2000

Intestinal absorption of peptides through the enterocytes.

Transport of intact peptides and proteins from the intestinal lumen into the blood is a unique phenomenon, which differs from the regular process of food digestion and absorption. Intestinal absorption of minute amounts of proteins is, however, being considered as a normal physiological process. It is thus important to define and understand the routes for protein transfer from the intestinal lumen to the blood and the mechanisms by which the macromolecules overcome the sieving barrier of the intestinal wall. The study on insulin has demonstrated that, upon proper introduction into the intestinal lumen, insulin is absorbed by the epithelial cells and transferred to the circulation. The peptides absorbed and transferred to the blood retained their biological activity and induced significant lowering of blood glucose levels. The efficiency of the absorption does not differ among the ileum, duodenum, and colon. Morphological examination demonstrated no alteration of the structural integrity of the epithelia, the enterocytes stay intact with well-developed microvilli, and the cells remain joined by tightly closed junctions. Application of immunocytochemistry on thin tissue sections revealed insulin antigenic sites at different locations depending on the time point. Insulin detected in the lumen of the intestinal tract is absorbed through the endosomal compartment of the epithelial cells rather than passing between cells. Internalization occurs through invaginations of the luminal plasma membrane and vesicular structures of the endosomal compartment. In 5-10 minutes, insulin is transferred to the basolateral membrane and released into the interstitial space to reach the circulation. Definition of the transcytotic pathway will contribute to a better understanding of drug delivery for potential therapeutic applications.

Animals↗
PubMed2006

Effect of P-glycoprotein on intestinal absorption and brain penetration of antiallergic agent bepotastine besilate.

The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the pharmacokinetics of bepotastine, intestinal absorption and brain penetration studies were performed. [(14)C]Bepotastine transport in P-gp-overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low, with a K(m) value of 1.25 mM. After i.v. administration, the brain/plasma free concentration ratio in mdr1-knockout mice was 3 times higher than that in wild-type mice. The in situ intestinal absorption studies of [(14)C]bepotastine in rats showed a clear regional difference, showing highest permeability at the upper part of small intestine with a decreasing permeability in the descending part of small intestine. The apparent absorption rate constant (ka) of [(14)C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [(14)C]bepotastine disappeared. The concentration dependence of ka of [(14)C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 microM). In conclusion, bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofenadine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗