In vitro/in vivo models for peptide oral absorption: comparison of Caco-2 cell permeability with rat intestinal absorption of renin inhibitory peptides.
Explore the source record for details and available documents.
Administration, Oral↗
SEARCH · Search PubMed
Results for “Intestinal Absorption”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Human biokinetics of strontium--part II: Final data evaluation of intestinal absorption and urinary excretion of strontium in human subjects after stable tracer administration.
Fractional intestinal absorption (f1 value) and urinary excretion of strontium in healthy human volunteers has been measured by simultaneous oral and intravenous administration of the stable isotopes 86Sr and 84Sr using the double-isotope method. Final evaluation of the complete data set confirmed that ingestion of different foodstuff and nutritional factors could influence the fractional gut uptake of strontium. In some cases, significant deviations from the f1 value adopted by the International Commission on Radiological Protection (ICRP) were found. The arithmetic mean (+/- standard deviation) of the f1 values of all experiments performed was determined to be 0.46 (+/- 0.24). The probability distribution function of the f1 values is represented by a lognormal curve with a geometric mean of 0.38 and a geometric standard deviation of 2.06. Urinary excretion in all subjects varied depending on the administered foodstuff in a wide range and differs from the ICRP model, up to 2 days after tracer administration. No age or gender dependence of the absorbed strontium fraction and of the urinary excretion of strontium after an oral load was found.
Administration, Oral↗
Stigmasterol reduces plasma cholesterol levels and inhibits hepatic synthesis and intestinal absorption in the rat.
Plant sterols compete with cholesterol (cholest-5-en-3beta-ol) for intestinal absorption to limit absorption and lower plasma concentrations of cholesterol. Stigmasterol (24-ethyl-cholesta-5,22-dien-3beta-ol; Delta(22) derivative of sitosterol [24-ethyl-cholest-5-en-3beta-ol]), but not campesterol (24-methyl-cholest-5-en-3beta-ol) and sitosterol, is reported to inhibit cholesterol biosynthesis via inhibition of sterol Delta(24)-reductase in human Caco-2 and HL-60 cell lines. We studied the effect of feeding 0.5% stigmasterol on plasma and liver sterols and intestinal cholesterol and sitosterol absorption in 12 wild-type Kyoto (WKY) and 12 Wistar rats. After 3 weeks of feeding, cholesterol and sitosterol absorption was determined in 6 rats from each group by plasma dual-isotope ratio method. After 3 more weeks, plasma and hepatic sterols and hepatic enzyme activities were determined in all rats. After feeding stigmasterol, baseline plasma cholesterol was 1.3 times and plant sterols 3 times greater in WKY compared with Wistar rats. Stigmasterol feeding lowered plasma cholesterol by approximately 11%, whereas plasma campesterol and sitosterol levels were virtually unchanged in both rat strains, and stigmasterol constituted 3.2% of plasma sterols in WKY rats and 1% in Wistar rats. After 6 weeks of feeding, cholesterol and sitosterol absorption decreased 23% and 30%, respectively, in WKY, and 22% and 16%, respectively, in the Wistar rats as compared with untreated rats. The intestinal bacteria in both rat strains metabolized stigmasterol to mainly the 5beta-H stanol (>40%), with only small amounts of 5alpha-H derivative (approximately 1.5%), whereas the C-22 double bond was resistant to bacterial metabolism. Hepatic stigmasterol levels increased from 11 microg/g liver tissue to 104 mug/g in WKY rats and from 5 microg/g liver tissue to 21 microg/g in Wistar rats. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was suppressed 4-fold in the WKY and almost 1.8-fold in Wistar rats, cholesterol 7alpha-hydroxylase activity was suppressed 1.6-fold in the WKY and 3.5-fold in Wistar rats, whereas cholesterol 27-hydroxylase activity was unchanged after feeding. In conclusion, stigmasterol, when fed, lowers plasma cholesterol levels, inhibits intestinal cholesterol and plant sterol absorption, and suppresses hepatic cholesterol and classic bile acid synthesis in Wistar as well as WKY rats. However, plasma and hepatic incorporation of stigmasterol is low.
Animals↗
Enhanced intestinal absorption of a hydrophobic polymer-conjugated protein drug, smancs, in an oily formulation.
Intestinal absorption of neocarzinostatin (NCS) and smancs (copolystyrene maleic acid-conjugated NCS), in aqueous and oily formulations, was investigated after oral administration in mice. Blood concentrations of NCS and smancs were determined with a cytotoxicity assay employing the highly sensitive Epstein-Barr (EB) virus-transformed B-lymphoblastoid cell line, TK/B. Smancs was more efficiently absorbed from a medium-chain triglyceride solution (oily smancs) than from an aqueous solution in phosphate-buffered saline (PBS). The maximum blood concentration and the area under the concentration curve versus time course (AUC) of oily smancs were 9 and 11 times greater than those of the aqueous form of smancs, respectively. At 5 hr after administration of oily smancs, 0.044% of the total smancs dose was found in blood, whereas the parent compound NCS was not detectable at any time. When oily smancs was administered orally to sarcoma 180 tumor-bearing mice, a selective accumulation of smancs in tumor tissue was observed. These results indicated that a biologically active protein, which cannot be used orally, may be rendered orally active drug by conjugation with a hydrophobic polymer in combination with an oily formulation.
Administration, Oral↗
[In vitro studies of intestinal absorption and biotransformation of furazolidone].
The intestinal biotransformation and absorption of the nitrofuran furazolidone were investigated in isolated gut cells and in the isolated perfused gut. In case of inhibiting furazolidone metabolism by high oxygen tension almost equal concentrations of the parent compound were measured on the mucosal and serosal side of the perfused gut segments. Lowering oxygen supply in order to adjust it to physiological conditions caused a complete degradation of furazolidone in isolated gut cells. Accordingly, hardly any unchanged furazolidone was detected on the serosal side of the isolated perfused gut. An open-chain cyanometabolite was formed in both systems indicating a reductive metabolic process which induces highly reactive intermediates. This metabolite also reached the serosal side of the gut representing the systemic circuit. Thus, the low systemic bioavailability is due to the considerable intestinal metabolism rather than a limited absorption. Unknown metabolites will reach the systemic circuit, the toxic potential of which is still obscure. Independent of its metabolic degradation, thus probably due to its redox cycle furazolidone inhibited intestinal functions as e. g. the flow of water and the transport of sodium.
Animals↗
Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of calcium in vivo.
Although it is well established that parathyroid hormone and phosphate are important regulators of 1,25-dihydroxyvitamin D [1,25(OH)2D] production, it remains unclear whether calcitonin affects vitamin D metabolism in vivo. Experiments were performed in the rat to determine the effect of chronic calcitonin infusion (0.2 U X h-1) on plasma levels of vitamin D metabolites and on calcium metabolism. Thyroparathyroidectomized animals fed a calcium-replete or calcium-free diet were studied for as long as 2 wk before they were killed. In control rats, a calcium-free diet alone for 12 d resulted in an increase in 1,25(OH)2D levels from 24 +/- 5 to 139 +/- 37 pg . ml-1, P = 0.025. The infusion of calcitonin also stimulated 1,25(OH)2D levels compared with controls on a regular diet (80 +/- 17 vs. 38 +/- 6 pg . ml-1, P less than 0.05) and on a calcium-free diet (460 +/- 50 vs. 139 +/- 37 pg . ml-1, P less than 0.001). In addition, calcitonin increased plasma calcium levels in animals on a regular diet by 50%; this effect was most likely due to increased intestinal absorption of calcium, because removal of calcium from the diet markedly blunted this effect. In contrast, calcitonin administration did not significantly affect 25(OH)D plasma levels. Collectively, these data suggest that calcitonin and calcium are independent regulators of 1,25(OH)2D production and that calcitonin stimulates intestinal absorption of calcium, by increasing circulating levels of 1,25(OH)2D.
Animals↗
[Small intestinal absorption in cancer patients--basis for enteral feeding therapy in oncology].
A deteriorating nutritional condition combined with the loss of body mass is one of the most noticeable symptoms of cancer. In order to answer the question to what extent absorption disorders in the small intestine are responsible for the malnutrition which develops, we studied 54 oncologic patients using modified D-xylose absorption tests. After the oral and intravenous administration of 10 g D-xylose at different times, the degree of absorption dependent on time was determined on the basis of a biophysical model. When accompanied by general nonspecific tumor symptoms, the frequency of absorption restrictions was increased. An established relation was found between the extent of small intestinal absorption, on the one hand, and the degree of spreading (staging) and the degree of histological differentiation of the carcinoma, on the other hand. Enteral absorption disorders represent a partial cause for the development of malnutrition in cancer patients and must be viewed as a result of a metabolic situation which is distinctly catabolic.
Adult↗
Zinc intestinal absorption in rats: specificity of amino acids as ligands.
The luminal phase of zinc intestinal absorption may be mediated by low-molecular-weight substances originated in digestive, metabolic or secretory processes. Amino acids are considered primary candidates for this role through the formation of complexes with zinc. However, structural characteristics that may be indispensable for this physiological function have not been explored in vivo. We investigated the comparative effectiveness of four amino acids and their respective chemically related homologues on the absorption of zinc by the jejunum, ileum and colon of the rat using a perfusion procedure. L-Tryptophan (Trp) allowed for significantly greater zinc absorption than tryptophol (Tpl) in all areas of the gut. L-Histidine (His) and imidazole (Imd) had similar effects in both the jejunum and the ileum. Imd allowed for much greater zinc absorption from the colon than did His (His, 388 +/- 31; Imd, 937 +/- 107 pmol/min X cm, P less than 0.001). Proline (Pro) was a more effective ligand than pyroglutamate (Pyr) in the ileum (Pro, 559 +/- 19; Pyr, 352 +/- 22 pmol/min X cm, P less than 0.001), but not in the jejunum or the colon. L-Cysteine was superior to N-acetyl-L-cysteine only in the ileum (508 +/- 45 vs. 348 +/- 25 pmol/min X cm, P less than 0.01). The greater zinc absorption achieved by amino acids than by non-amino acid homologues in the small intestine appeared to be due to the presence of both mediated and nonmediated transport mechanisms for amino acids but of only nonmediated zinc uptake for the homologues. In the colon, where amino acid absorption does not take place, high structural affinity for zinc, such as that exhibited by Imd, allowed for considerable absorption of the trace element.
Acetylcysteine↗
HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer.
The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans. The similarity of both the diffusion coefficients and permeability values obtained for a range of hydrophilic and lipophilic compounds in the two models indicates that the mucus layer secreted by the human adenocarcinoma HT29-MTX goblet cells does not constitute a diffusion barrier to such compounds. The lack of P-glycoprotein (P-gp) in the HT29-MTX cell line may explain the higher permeability values obtained for cimetidine and sumatriptan in this model compared with those derived from the Caco-2/TC7 monolayers. The results suggest that the HT29-MTX model can be used to rank order the passive permeability of compounds, irrespective of their potential interaction with P-gp, which may facilitate optimization of the physicochemical features of compounds within a chemical series.
Administration, Oral↗
Modelling intestinal absorption of salbutamol sulphate in rats.
The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium between salbutamol sulphate concentrations in lumen and enterocyte, and the salbutamol sulphate absorption was best described by a simultaneous passive diffusion (ka = 0.636 h(-1)) and active absorption (VMax = 0.726 mM/h, Km = 0.540 mM) processes from intestinal lumen to enterocyte, together with an active capacity-limited P-gp efflux (V'max = 0.678 mM/h, K'm = 0.357 mM) from enterocyte to intestinal lumen. The extent of salbutamol sulphate absorption in rat small intestine can be improved by NaN3, grapefruit juice and verapamil.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Studies on the mechanism of intestinal absorption of sugars. 8. Cation inhibition of active sugar transport and 22Na influx into hamster small intestine, in vitro.
Explore the source record for details and available documents.
Animals↗
The influence of ionizing radiation on intestinal absorption of amino acids and their incorporation into proteins of the mucous membrane of the small intestine.
Explore the source record for details and available documents.
Animals↗
Intestinal absorption of amino acid derivatives: importance of the free alpha-amino group.
The intestinal absorption of L-lysine-p-nitroanilide, L-alanine-p-nitroanilide, and glycine-p-nitroanilide was studied in the presence of competitive inhibitors in a perfused rat intestine. It ws observed that L-lysine-p-nitroanilide absorption was inhibited by L-lysine methyl ester and L-arginine-beta-naphthylamide but not by N alpha-acetyl-L-lysine methyl esters. L-Alanine-p-nitroanilide absorption was inhibited by L-alinine methyl ester but not by beta-alanine methyl ester. It was further observed that N alpha-benzoyl-L-arginine-p-nitroanilide and N alpha-succinyl-L-phenylalanine-p-nitroanilide were poorly absorbed. It was concluded that the peptidase in the brush border region that serves as the hydrolysis site requires a free alpha-amino group (an aminopeptidase), and that passive absorption of these compounds occurs only to a small extent.
Amino Acids↗
Intestinal absorption of free oleic acid in the unanesthetized rat: evidence for a saturable component?
The intestinal absorption of free oleic acid at low intraluminal concentrations and the influence of luminal factors on its absorption were studied in the unanesthetized rat. The relationship between oleic acid concentration (30-2500 microM) and its rate of absorptions fitted best to a rectangular hyperbola (y = x/(2.19 + 0.0015x), r = 0.94). Oleic acid's rate of absorption increased as the hydrogen ion and sodium taurocholate concentrations were increased or as the thickness and resistance of the unstirred water layer were diminished or following the addition of lysolecithin. The additions of the artificial detergent Tween-80, or lecithin and linoleic, linolenic and arachidonic acids to the perfusate decreased oleic acid's rate of absorption. It was concluded that oleic acid absorption in this range of concentrations displays apparent saturation kinetics which are due to unstirred layer effects, limited aqueous solubility of oleic acid and possible saturation of cytosol fatty acid binding proteins. Factors which increase oleic acid's protonated concentration or diminish the unstirred layer resistance, enhance its absorption rate, while factors which enhance its micellar solubility or interfere with its transfer out of the cell membrane decrease its overall rate of absorption.
Animals↗
Wheat bran and wheat germ: effect on digestion and intestinal absorption of dietary lipids in the rat.
We investigated the effects of fiber-rich wheat bran and wheat germ on dietary fat and cholesterol assimilation. Rats were given a test meal containing [14C]triolein and [3H]cholesterol. After various digestion periods, addition of the wheat fractions (10% of meal solids) did not modify the lipid gastric emptying rate. Gastric and intestinal triglyceride lipolysis was significantly reduced when wheat fractions were present. The mucosal uptakes of [14C]lipids and [3H]cholesterol were significantly modified by the wheat fractions after 1 and 2.5 h. No shift in the site of intestinal absorption and no change in the distribution of labeled lipid in the intestinal mucosa was observed. Plasma [14C]lipids and [3H]cholesterol were significantly decreased by both wheat fractions whereas these increased cecal accumulation of dietary lipids and cholesterol. Thus wheat bran and wheat germ alter fat and cholesterol processing in rats. A mechanism of action accounting for the data observed in proposed.
Animals↗
Effect of low calcium and low phosphorus diets on the intestinal absorption of water in intact and parathyroidectomized pigs.
Young pigs, each surgically prepared beforehand with a Thiry-Vella loop of jejunum, were used to study the effect of feeding low calcium and low phosphorus diets on the intestinal absorption of water. Feeding a low phosphorus diet caused a highly significant stimulation in the absorption of water in parathyroid gland-intact and parathyroidectomized pigs; low calcium diets were without effect.
Animals↗
Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781.
The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.
Anilides↗
INTESTINAL ABSORPTION OF BILE SALTS IN THE RAT.
Explore the source record for details and available documents.
Bile Acids and Salts↗