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PubMedDate not supplied

Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis.

INTRODUCTION: The aim of this investigation was to evaluate methods for increasing Caco-2 cell throughput for assessing drug intestinal absorption. The use of 6-, 12-, and 24-well membranes and the effect of membrane size on permeability and the integrity of the Caco-2 cell monolayer were assessed. In an effort to optimize the assessment of drug permeability, increased throughput was investigated by testing compounds singly or as mixtures of analytes. METHOD: The transepithelial electrical resistance (TEER) of cell monolayers was measured on 0.33, 1.0, and 4.7 cm2 polycarbonate membranes using EVOM, over a 25-day period. Absorptive transport was determined on all compounds tested using LC-MS/MS assays, or liquid scintillation spectrometry. RESULTS: The effect of multiple compounds in one well compared to single compounds was assessed with atenolol, nadolol, metoprolol, and propranolol for mixtures of four compounds and with RWJ-53308, atenolol, terbutaline, propranolol, naproxen, piroxicam, topiramate, and furosemide for mixtures of eight compounds. The apparent permeability (Papp) values correlated well between single analytes and mixtures of four and eight analytes in each well. Drug permeability decreased slightly with an increase in well size. The TEER value increased with the number of days in culture for each of the 6-, 12-, and 24-well sizes. DISCUSSION: It was demonstrated that the 24-well format system is ideal for high-throughput assessment. Furthermore, the approach of mixing four or eight analytes in each well to further increase throughput was also demonstrated to be valid.

Caco-2 Cells↗
PubMed2002

Prediction of intestinal absorption: comparative assessment of GASTROPLUS and IDEA.

We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery.

Intestinal Absorption↗
PubMed1997

Intestinal absorption screening of mixtures from combinatorial libraries in the Caco-2 model.

PURPOSE: Understanding how chemical structures influence transport across the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationships between structure and transport, six arbitrary mixtures of N-substituted glycine (NSG) peptoids containing 24 physicochemically diverse compounds were evaluated in the Caco-2 model of intestinal absorption. METHODS: Samples were analyzed by HPLC and the areas of the peaks representing the components of each mixture were summed to measure "aggregate" apparent permeability coefficients (Papp), a score of the influence of the common structural element within each mixture towards absorption. Mass spectrometry was used to identify the chemical structure of Caco-2 permeable compounds. RESULTS: Three linear trimeric mixtures were examined and, for each mixture, none of the components was detected in receiver chambers. It was concluded that the components of these mixtures each had a Papp value less than 0.8 x 10(-6) cm/sec, a permeability less than mannitol. Three dimeric mixtures were examined and they exhibited aggregate P(app) values of 9.2 x 10(-6), 14 x 10(-6) and 6.9 x 10(-6) cm/sec. These transport rates reflected the transport of most of the components of each mixture. Furthermore, the components of the dimeric mixtures which were transported at a rate greater than mannitol were apparently transported by passive mechanisms. CONCLUSIONS: This study demonstrated that mixtures can be used to study structure-transport relationships in the Caco-2 model. The information obtained from this type of study will be integrated into the design of future chemical libraries. Other potential uses of chemical mixtures with the Caco-2 model are also discussed.

Biological Transport, Active↗
PubMed1996

Improvement of intestinal absorption of leucine enkephalin by sugar coupling and peptidase inhibitors.

Peptidase-degradable leucine enkephalin (LE) was coupled with cellobiose or gentiobiose. In the absorption experiments, cellobiose-coupled LE (CcpLE) was more stable than LE itself on the mucosal side, and CcpLE appeared on the serosal side. Destyrosyl LE coupled with cellobiose was not formed, indicating that sugar coupling provided LE with aminopeptidase resistance. In the presence of inhibitors of angiotensin-converting enzyme and enkephalinase, the stability of CcpLE on the mucosal side was increased, and as a result more was absorbed. Furthermore, the absorption clearance was much higher than the value expected from the mucosal concentration of CcpLE. Similar results were observed in the absorption of gentiobiose-coupled LE. In the LE absorption experiment, however, LE was not detected on the serosal side even in the presence of these peptidase inhibitors. Improvement of intestinal absorption by sugar coupling and peptidase inhibitors was evaluated kinetically, indicating the exclusive contribution of metabolic degradation of LE through intestinal tissues to the absorption process.

Animals↗
PubMed1990

Intestinal absorption of retinol and retinyl palmitate in the rat. Effects of tetrahydrolipstatin.

The aim of the present study was to characterize the intestinal absorption of retinol and retinyl palmitate in thoracic duct and bile duct fistulated rats and to investigate the effect of a simultaneously administered lipase inhibitor, tetrahydrolipstatin (THL). Absorption was determined as lymphatic recovery over a 24-hr period, including an initial 12-hr continuous intraduodenal infusion of either [11,12-3H]retinol or [11,12-3H]retinyl palmitate given in emulsified glyceryl trioleate or in mixed micellar solution of monoolein and oleic acid. From micellar dispersion, labeled retinol and retinyl palmitate were recovered in the lymph to 50-60% and both to the same extent. Administered in emulsified form, labeled retinol from fed retinyl palmitate was recovered to 47%, but retinol from fed retinol to only 18%. THL (10(-4) M) in the infusate had no significant effect on the recovery of 14C-labeled oleic acid. The recovery of label from emulsified glyceryl tri[1-14C]oleate was significantly decreased at this concentration of THL (76.5% vs 19.6% recovery). When administered in emulsified form, retinol absorption was not significantly affected by THL at 10(-4) M, while retinyl palmitate absorption was very significantly decreased (5.0% compared to 47.8%). In the presence of THL, retinol absorption from retinyl palmitate in micellar solution was decreased (from 58% to 17%). Most of the retinol in the lymph extracts (72.2 to 91.3) was present as retinyl ester, regardless of the chemical and physical form of administration. Furthermore, THL did not induce any change in this pattern.

Animals↗
PubMed2005

Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption.

The absorption characteristics of temocapril were investigated using Caco-2 cells, and the esterases expressed in Caco-2 cells were identified. Temocapril was almost completely hydrolyzed to temocaprilat during transport across Caco-2 cells. Hydrolysis experiments of temocapril in Caco-2 cell 9000g supernatant (S9) and brush-border membrane vesicles showed that temocapril was mainly hydrolyzed within the cells after uptake, after which the temocaprilat formed was transported to both the apical and basolateral surfaces. In native polyacrylamide gel electrophoresis by detection of hydrolase activity for 1-naphthylbutyrate, Caco-2 cell S9 showed a band with high esterase activity and another band with extremely low activity. The proteins in the major and minor bands were identified as carboxylesterase-1 (hCE-1) and carboxylesterase-2 (hCE-2). The abundant expression of hCE-1 in Caco-2 cells was supported by reverse transcription-polymerase chain reaction. In the normal human small intestine, hCE-2 is abundantly present, although the human liver expresses much higher levels of hCE-1 and lower levels of hCE-2. The expression pattern of carboxylesterases in Caco-2 cells is completely different from that in human small intestine but very similar to that in human liver. Since the substrate specificity of hCE-1 differs from that of hCE-2, it is suggested that the prediction of human intestinal absorption using Caco-2 cell monolayers should be performed carefully in the case of ester- and amide-containing drugs such as prodrugs.

Caco-2 Cells↗
PubMedDate not supplied

Effect of starvation on the in vivo intestinal absorption of sugars and amino acids in young chickens (Gallus domesticus).

The effect of different patterns of starvation (acute and intermittent) on the in vivo intestinal absorption of glucose and tryptophan during the first days of Gallus domesticus chicks life was measured. Both acute and intermittent starvation increase duodenal absorption of glucose and jejunal absorption of tryptophan. Intermittent starvation tends to reduce the effect of age which normally decreases intestinal uptake of nutrients. This effect is clearer for glucose absorption than for tryptophan absorption.

Animals↗
PubMed1983

Effect of colchicine on rat small intestinal absorptive cells. I Formation of basolateral microvillus borders.

Treatment of rats with colchicine (0.5 mg/100 g of body weight) for more than 3 hr causes formation of microvillus borders along lateral and basal surfaces of absorptive cells in the small intestine. Morphologically, these strongly resemble the apical brush border inclusive of the terminal-web region. Formation of basolateral microvilli is restricted to mature absorptive cells. At 6 hr after administration of colchicine, 3.47% (+/- 1.94%) of the basolateral cell surfaces exhibit "implantation" of microvillus borders. The results show that colchicine induces formation of surface differentiations at lateral and basal surface regions that are restricted to the apical cell surface in controls. Redistribution of constituents of the plasma membrane from apical to basolateral membrane portions, as well as rearrangement in the organization of microfilaments can be considered to underlie formation of basolateral microvillus borders. From the antimicrotubular effect of colchicine it may be deduced that microtubules exert a regulative function in the formation of surface differentiations on absorptive cells of the small intestine and in the maintenance of the polarity of the cells.

Animals↗
PubMed1976

[Intestinal absorption from therapeutic iron doses (author's transl)].

On a total of 105 persons with normal iron stores, iron depletion, and iron deficiency the intestinal absorption from therapeutic iron doses (100 mg Fe and 50 mg Fe as ferrous glycocoll sulphate) of a special galenic form was measured. The measurements were performed by means of a whole-body counter and preparations labelled with radio-iron (59Fe). Mean values of absorption rates from 100 mg Fe in healthy males were 5.0% and in healthy females 5.6% whereas in latent iron deficiency and in iron deficiency anemia mean values of 10% and 13% were obtained, respectively. The maximum absorption rate of 20 to 25% is reached already in the late stage of latent iron deficiency. Advancing severeness of iron deficiency is not followed by an increase of iron absorption. Investigations on 21 persons showed no significant difference between absorption rates of the galenic preparations used when administered orally before or after breakfast, respectively.

Anemia, Hypochromic↗
PubMed2006

Partially hydrolyzed guar gum increases intestinal absorption of iron in growing rats with iron deficiency anemia.

OBJECTIVE: The objective of this study was to evaluate the effect of partially hydrolyzed guar gum (PHGG) dietary fiber towards intestinal iron absorption, for dietary intake and on the growth of rats with iron deficiency anemia in comparison to those fed on a diet with cellulose and without dietary fiber. MATERIALS AND METHODS: Male Wistar rats (n=24) weaned at 21 days were fed with AIN93-G diet without iron for 2 weeks in order to induce iron deficiency anemia. At 36 days old, the anemic rats were divided into three groups: (1) PHGG group-100g of PHGG per kg of diet; (2) Cellulose group-100g of cellulose per kg of diet; (3) Control group-diet without dietary fiber. All the diets had 25mg of elemental iron/kg of diet added to lead to recovery from iron deficiency anemia. RESULTS: The final hemoglobin values in g/dl, for the PHGG group, the cellulose group and the control group were, respectively: 11.3+/-1.2, 8.6+/-0.7 and 8.1+/-0.9 (P<0.001). The levels of hepatic iron, in mug/g of dry tissue, in the same order, were: 322.2+/-66.6, 217.2+/-59.1 and 203.7+/-42.4 (P<0.001). Apparent iron intestinal absorption was, respectively: 67.5+/-8.9%, 35.4+/-15.3% and 31.3+/-24.9% (P<0.001). The three groups consumed similar quantities of diet. The changes in weight and in body length were similar in the three groups studied. CONCLUSION: PHGG led to greater intestinal absorption of iron, regeneration of hemoglobin and hepatic levels of iron than diet with cellulose and diet control.

Anemia, Iron-Deficiency↗
PubMed1976

Intestinal absorption of calcium from three commerical calcium preparations in man.

Intestinal 47Ca absorption was determined from blood and stool radioactivity after oral administration of 150 ml saline containing the isotope (as 47CaCl2) and 500 mg of elementary calcium in the form of one of three commercial calcium preparations from "NAF" or "Collett" (containing calcium carbonate) or from "Sandoz" (containing mainly calcium lactogluconate). 51CrEDTA was used as unabsorbable marker to allow corrections for incomplete faecal collection. The calcium carbonate preparations were only partially dissolved when administered, but the calcium absorption from these preparations was found to be no less than that from the completely soluble calcium "Sandoz" preparation. The calculated minimal absorption of calcium was, on an average, about 100 mg from all three calcium preparations in subjects without known intestinal calcium absorption defects.

Administration, Oral↗
PubMed1988

Effects of fusarenon-X and T-2 toxin on intestinal absorption of monosaccharide in rats.

In order to delineate the effects of Fusarenon-X (FX) and T-2 toxin (T-2) on intestinal absorption of monosaccharide, jejunal absorption in vivo and uptake in vitro of 3-0-methyl glucose (m-glucose) and L-glucose were studied in rats. Jejunal absorption in vivo was assessed by determining the rate of appearance of the sugars in plasma of the mesenteric vein draining the jejunal segment, which was perfused with the medium containing radiolabelled m-glucose or L-glucose. Jejunal uptake in vitro was assessed by determining the m-glucose or L-glucose uptake by the everted jejunum taken from toxin-treated rats. m-Glucose absorption was reduced 1 or 3 h after either toxin was injected into the jejunal lumen. A reduction of m-glucose absorption was also noted after intravenous injection of the toxins, although the timing and magnitude of the reduction were slightly different from those seen after the luminal injection. These results suggest that both toxins impair the jejunal function relating to monosaccharide absorption in the early stages of intoxication. The reduction in m-glucose absorption was associated with a reduction in L-glucose absorption and unchanged or increased uptake of L-glucose. The active transport component, which was indicated by the difference between absorption or uptake of the two sugars, was also reduced in association with the reduction of m-glucose absorption. These results suggest that the toxins cause specific damage in the active transport system for monosaccharides on the one hand, and impairment of their diffusional movement from the epithelial layer to the mesenteric vein on the other.

3-O-Methylglucose↗
PubMed1990

Intestinal absorption of D-xylose in the early post-operative period.

To assess intestinal absorption in the early post-operative period, portal and subclavian vein catheters were implanted into 8 pigs. For direct d-xylose infusion into the upper small intestine a feeding tube was inserted via a gastrostomy. Four control animals (Group 1) underwent an open and close laparotomy after catheter and tube implantation. Four pigs (Group 2) underwent a standardised ileocoecostomy. At 6, 24, 36, 48 and 72 h after surgery, d-xylose was infused into the small intestine in both groups of animals. After single-dose administration the absorption kinetics were measured in the pre- and post-hepatic blood compartment. With increasing time after operation the rate and extent of d-xylose absorption returned towards normal but there were significant differences in the d-xylose kinetics between the two groups. The absorption kinetics and d-xylose uptake recovered more rapidly in the control group than in those who underwent ileocoecostomy. Effective enteral feeding in controls after 36 h was achieved, but in Group 2 was delayed until 48 h post-operatively. Absorption capacity returned to normal after 48 h in controls and after 72 h in Group 2.

Journal Article↗
PubMed2000

Intestinal absorption and excretion of troglitazone sulphate, a major biliary metabolite of troglitazone.

1. Deconjugation by sulphate transfer and intestinal absorption of troglitazone sulphate (M1), the major metabolite of a thiazolidinedione antidiabetic drug, troglitazone, were studied in the male F344 rat using 14C-troglitazone, 4C-M1 and 35S-M1. 2. Some part of M1, produced in the liver and excreted mostly in the bile, was deconjugated in the intestine to the parent compound, troglitazone, by arylsulphate sulphotransferase originated from intestinal flora. However, deconjugation of M1 was not catalyzed by arylsulphatases. Caecal injection of M1 led to the appearance of troglitazone and M1 in plasma. 3. Biliary excretion mostly as M1, and, following absorption, as M1 and troglitazone after deconjugation, were indicated as the basis for the enterohepatic circulation of troglitazone. 4. Enterohepatic circulation may prolong the pharmacological effects of troglitazone.

Animals↗
PubMed1991

[Ruminal digestion and intestinal absorption of lupine proteins extruded in the lactating cow].

Four lactating cows fitted with permanent ruminal, duodenal and ileal cannulae were used to study the effect of extrusion of whole lupin seeds at 195 degrees C (Lupinus albus cv Lublanc) on organic matter (OM) and nitrogen (N) degradation in the rumen and their flow to and absorption from the small intestine. Raw whole lupin seeds (RWLS) and extruded whole lupin seeds (EWLS) were fed in diets containing 15.5% crude protein and composed of 22.6% whole lupin seeds, 56.5% corn silage, 10.2% corn grain and 10.7% Italian ray-grass on a DM basis, supplemented with vitamins and minerals. Chromium ethylenediaminotetraacetic (Cr-EDTA) and ytterbium chloride (YbCl3) were used as liquid and particulate markers respectively, while purines and 15N ammonium sulfate were utilized as bacterial markers. Cows fed EWLS had a similar ruminal ammonia N and volatile fatty acid concentrations and efficiency of bacterial protein synthesis compared to those fed the RWLS diet. Total tract OM and N digestion were not affected by inclusion of EWLS instead of RWLS; the corresponding mean values were 70 and 71%. Apparent degradation of OM and N in the rumen were 44 and 64% for diets containing RWLS, and 40 and 39% for EWLS diets. Feeding diets including EWLS both increased non ammonia N and dietary N flow to the duodenum compared with diets containing RWLS (472 vs 357 g/d) and (263 vs 153 g/d) respectively. Absorption from the small intestine (g/d and % entering) of dietary N was higher for EWLS diets (146 vs 62 g/d; 34 vs 15%). The PDIA, PDIE and PDIN contents (g/kg of DM) of RWLS were 18, 94 and 245 respectively; the corresponding values after extrusion were 145, 220 and 220.

Animal Feed↗
PubMed1970

Studies on inhibition of intestinal absorption of radioactive strontium. IX. Relationship between biological activity and electron microscopic appearance of alginic acid components.

The inhibitory action of alginate on intestinal absorption of radioactive strontium was investigated in order to correlate the biological activity with the chemical composition. Alginate from Laminaria hyperborea was partially hydrolyzed with oxalic acid and the degradation products were fractionated into polymannuronic and polyguluronic acid. The activity of these products was assessed biologically in rats and morphologically by electron microscopy. Sodium polymannuronate was found to be less effective than sodium polyguluronate in preventing absorption of radiostrontium. The inhibition of absorption of radio-calcium was low and not affected by hydrolysis or fractionation. When dried from dilute aqueous solutions, the polymannuronate retained the original helical structure of alginate, while the polyguluronate showed a strong tendency to coagulate, forming granules. The variation in the biological activity was attributed to the morphological differences between these alginic acid components and it is suggested that the degree of uncoiling of the polyguluronate chain in water is greater than that of the polymannuronate chain, thus making the carboxylate ions more accessible to strontium.

Alginates↗