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PubMed1986

Comparison of the effect of two different hypoglycemic agents, glibenclamide and HB 699, on the rat small intestinal absorption of sugars and amino acids.

4-(2-[5-Chloro-2-methoxy-benzamido]-ethyl)-benzoic acid (HB 699) belongs to the group of hypoglycemic benzoic acid derivatives. Although lacking the sulfonylurea group, the structure of HB 699 partly resembles that of glibenclamide which is known to impair small-intestinal glucose absorption in vitro at high concentrations. Whereas this intestinal effect of glibenclamide is unlikely to contribute to its blood-glucose lowering properties, extrapancreatic and particularly intestinal effects may be important for the antidiabetic action of HB 699. Thus, HB 699 was compared with glibenclamide for the effect on the small-intestinal absorption of sugars and amino acids in vitro (everted-sac and tissue-accumulation technique) and in vivo (single-pass perfusion of the jejunum). In vitro both drugs inhibited the active transport of sugars and amino acids in a dose dependent manner. At equieffective doses (HB 699, 4.5 mmol/l and glibenclamide, 1 mmol/l) the mode of inhibition by the two drugs was similar. A 30-min incubation period reduced the uptake of methyl alpha-D-glucoside by about 75%. The degree of inhibition depended on the time of exposure of the tissue to the drugs. In vitro kinetic studies revealed a mixed type of inhibition. The in vivo effect of the drugs was in accordance with the in vitro findings. Inhibition, as in vitro, was not reversible and even increased further after reinfusion of a drug-free perfusate. In vivo, the drugs inhibited the absorption of methyl alpha-D-glucoside and leucine only at low (less than 20 mmol/l) but not at high (greater than 30 mmol/l) solute concentrations. These results indicate that hypoglycemic benzoic acid derivatives may exert their blood-glucose lowering properties in part by impairing the small-intestinal active transport of glucose.

Amino Acids↗
PubMed1990

Intestinal absorption of carnitine in experimental azotemia.

We studied carnitine absorption in rats rendered azotemic by subtotal nephrectomy (RF) and compared the results with those obtained in a sham-operated group on liberal food intake (NL) and those pair-fed (PF) with the RF group. Animals with short-term (2 weeks post-nephrectomy) and long-term (5-6 weeks post-nephrectomy) RF were studied. In vivo recirculating perfusion was used. A significant reduction in carnitine absorption (expressed per unit length) was noted in the short-term RF and PF groups when compared to the NL controls. When the data were corrected for intestine weight, the short-term RF and PF groups showed comparable absorption rates with the NL group. These findings suggest that in animals with short-term RF, weight loss is responsible for the observed alteration in carnitine absorption. Intestinal segments from PF and short-term RF animals had significantly greater carnitine accumulation suggesting decreased release into the circulation. In the long-term RF setting, RF and PF animals demonstrated reduced carnitine absorption. When the data were expressed per unit of weight the absorption rates normalized, implicating reduced intestinal mass as the factor responsible for reduced carnitine absorption. No significant difference was found in the amount of residual carnitine suggesting amelioration of impaired transport out of the enterocyte in chronic RF.

Animals↗
PubMed1995

Effect of intraamniotic dexamethasone administration on intestinal absorption in a rabbit gastroschisis model.

Infants with gastroschisis experience delayed intestinal motility and absorption for several weeks after birth. This intestinal dysfunction is believed to occur primarily in the third trimester and to be largely caused by the prolonged exposure of the intestine to amniotic fluid. Previous studies have shown that prenatal steroid administration will enhance mucosal disaccharidase activity and nutrient uptake. The present study evaluates the effects of dexamethasone on intestinal function in a rabbit fetal gastroschisis model. Thirty-four fetuses from 10 New Zealand white rabbits were divided into three groups: (1) gastroschisis group (GSC, n = 10), gastroschisis was created on gestational day (GD) 24 (term = 31 to 33 days); (2) dexamethasone group (GSD, n = 10), after the creation of gastroschisis, a small osmotic pump was placed into the rabbit doe for dexamethasone infusion into the fetal amniotic cavity for 7 days (0.2 microgram/g/d); (3) normal group (NF, n = 10), unoperated littermates from the GSC group. There were no maternal deaths, and fetal survival rate was 85%. The fetal small intestinal disaccharidase enzyme, lactase (UE/g protein), was markedly decreased in GSC fetuses. It was increased 70% in the GSD group but lower than in normal fetuses (GSC = 10.0 +/- 1.6; GSD = 17.3 +/- 1.6 [GSD versus GSC, P < .05]; NF = 48.0 +/- 6.7). Maltase activity in the GSD group was significantly increased (GSC = 7.2 +/- 1.1; GSD = 13.9 +/- 1.8 [GSD versus GSC, P < .05]; NF = 12.2 +/- 1.3).(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Muscles↗
PubMed2005

Prediction of gastro-intestinal absorption using multivariate adaptive regression splines.

Multivariate adaptive regression splines (MARS) and a derived method two-step MARS (TMARS) were used for modelling the gastro-intestinal absorption of 140 drug-like molecules. The published absorption values for these molecules were used as response variable and calculated molecular descriptors as potential explanatory variables. Both methods were compared and their potential use in quantitative structure-activity relationship (QSAR) context evaluated. The predictive abilities of the models were studied using different sequences of Monte Carlo cross validation (MCCV). It was shown that both types of models had good predictive abilities and that for the data used, MARS gave better results than TMARS. It could be concluded that both methods could be valuable for QSAR modelling.

Algorithms↗
PubMed2002

A simple new method to calculate small intestine absorptive surface in the rat.

The rat is an established model for studying intestinal adaptations following abdominal surgery. In the study of functional and morphological adaptations of the small intestine, it is helpful to estimate the mucosal surface area. In order to simplify measurements and calculation we developed a new mathematical model for calculation of the mucosal surface area on histological sections. In contrast to other methods, it requires only cross-sections of small intestine and includes the measurement of only three histological parameters: length and width of villus and width of crypt. The new approach was compared with the most commonly used procedures, the Harris and the Fisher-Parsons methods, under experimental conditions. An animal study including single-pass perfusion, fixation, staining and subsequent histomorphometry of jejunum and ileum using these different methods was performed. The new method showed the least work and presented no significant differences compared with the precise Harris method. In conclusion, the method described is an adequate tool to estimate the mucosal surface area with less work and with comparable results to established methods. The less-complex method may be a valuable tool in experimental research of small intestine adaptations in rats.

Animals↗
PubMed1982

FMN phosphatase and FAD pyrophosphatase in rat intestinal brush borders: role in intestinal absorption of dietary riboflavin.

Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), are two major coenzyme forms of dietary riboflavin. Yet little attention has been given to the release of the vitamin from its coenzyme forms during the absorptive process. Homogenates from rat intestine catalyze the hydrolases of these flavin coenzymes. To determine the location of FMN and FAD hydrolases, homogenates of intestinal mucosa were fractioned. FMN and FAD phosphatases were localized in brush border membranes. FAD pyrophosphatase activity was maximal at pH between 6.5 and 8.5 while FMN phosphatase has a pH optimum of 7.5 - 8.0. FAD pyrophosphatase is more stable to heat. The two enzymes separate on ion exchange chromatography of an isobutanol extract of intestinal brush border membrane fraction. Inhibition of 14C-riboflavin uptake by FMN and FAd in everted rings of rat intestine is directly related to the amount of conversion of these coenzymes to free riboflavin by intestinal enzymes. When FMN and FAD conversion to riboflavin is inhibited by EDTA, competition with 14C-riboflavin for transport was correspondingly decreased. These studies are best explained by a sequential process in which hydrolysis of FMN and FAD by enzymes of the intestinal brush border is followed by absorption of free riboflavin.

Animals↗
PubMed1997

[Delivery system design for improvement of intestinal absorption of peptide drugs].

Most people drugs are hydrophilic molecules with a molecular weight between 300 and 20,000 and such molecules are usually given by parenteral administration. In many cases, enteral administration of these peptides via the gastrointestinal tract is preferred. However, oral administration of peptides and proteins is often limited by their instability in the gastrointestinal environment and/or poor absorption from the gut. To promote the absorption of these drugs, we first discovered unsaturated fatty acids with absorption enhancing activities and less harmful properties to the gastrointestinal membranes in hydrolysates of natural oil. The mechanisms whereby the permeability of drugs was enhanced by the fatty acids are associated with the disorder in the membrane's interior and the interaction of these fatty acids with the polar head group of phospholipid. Furthermore, we suggested that a SH-related substance was involved in the permeability enhancing effect of these fatty acids. Secondly, we developed a lympho-targeting delivery system for bleomycin by the combined effects of an ion-pair complex with dextran sulfate (DS) and an absorption enhancer. We found a very high lymphatic concentration when administered bleomycin-DS together with the absorption enhancer. Its mechanism may be due to a molecular sieving in the blood-lymph barrier in the intestinal tissues. Finally, to improve the intestinal absorption of peptides, we synthesized novel lipophilic derivatives of peptides including TRH (thyrotropin releasing hormone), tetragastrin, enkephalin, calcitonin and insulin by a chemical modification with fatty acids, while maintaining their pharmacological activities. The stability and permeability of these peptides were improved by acylation with some fatty acids having appropriate carbon numbers. Thus, we have established the strategies for improving the delivery of peptide drugs by various approaches. In future, the combination use of these approaches will be expected to develop the delivery systems of these drugs for therapeutic treatment.

Acylation↗
PubMed1980

Diflubenzuron: intestinal absorption and metabolism in the rat.

1. The metabolic fate of the insecticide diflubenzuron was investigated in the rat with radioactively labelled forms of the compound. 2. Intestinal absorption, measured as the sum of urinary and biliary excretion, diminished greatly with increasing dose, from about 50% at 4 mg/kg to about 4% at 900 mg/kg. 3. Excretion was almost complete at 72 h after dosing. At that time up to 4% of a dose was recovered from the carcasses of the rats. No detectable excretion of radioactive CO2 occurred (less than 0.5% of dose). 4. The metabolic pattern in urine and bile was investigated with diflubenzuron labelled with both 3H and 14C. No unchanged compound was detected. About 80% of the metabolites appeared to have the basic diflubenzuron structure intact. Three of these, hydroxylated at either aromatic ring, were identified; they were largely excreted as conjugates in the bile. The remainder, also largely excreted in the bile, constituted very polar material. About 20% of the diflubenzuron underwent scission of the ureido bridge. One scission product, 2,6-difluorobenzoic acid, was largely excreted as such in the urine. Its counterpart, 4-chlorophenylurea, was not present in urine or bile in appreciable quantity; nor was 4-chloroaniline detected.

Animals↗
PubMed1999

Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption.

A method for the rapid computation of polar molecular surface area (PSA) is described. It is shown that consideration of only a single conformer when computing PSA gives an excellent correlation with intestinal absorption data-as good as previously reported methods employing multiple conformers. Circumventing a time-consuming conformational analysis opens the possibility of computationally screening large numbers of compounds for problems relating to absorption prior to synthesis. The robustness of the criterion for identifying poorly absorbed compounds (PSA >/= 140 A(2)) is illustrated through its application to a diverse test set of 74 drugs. The PSA-based method is also compared to an experimental method for absorption prediction recently described in the literature.

Chemical Phenomena↗
PubMed2004

Intestinal absorption of p-coumaric and gallic acids in rats after oral administration.

Ferulic acid (FA) and p-coumaric acid (CA) are absorbed by the monocarboxylic acid transporter (MCT) in Caco-2 cells, although gallic acid (GA) is not. Therefore, the MCT is selective for certain phenolic acids. Absorption of orally administered CA and GA in rats was studied to obtain serum pharmacokinetic profiles and to investigate their intestinal absorption characteristics in vivo. Rats were administered 100 micromol/kg body weight of CA and GA, and blood was collected from the portal vein and abdominal artery after administration. CA, GA, and their metabolites were quantified with a highly selective and sensitive coulometric detection method using high-performance liquid chromatography-electrochemical detection. Ingested CA was rapidly absorbed in the gastrointestinal tract in an intact form. The serum concentration of intact CA in the portal vein peaked 10 min after dosing (C(max) was 165.7 micromol/L). In contrast, GA was slowly absorbed, with a t(max) for intact GA of 60 min and a C(max) of 0.71 micromol/L. The area under the curve for intact CA and GA was calculated from the serum concentration profile in the portal vein to be 2991.3 and 42.6 micromol min L(-)(1), respectively. The relative bioavailability of CA against GA was about 70. This is the first demonstration that absorption efficiency of CA is much higher than that of GA in vivo. The absorption characteristics of CA are clearly different from those of GA. These findings are in good agreement with the results obtained in vitro using a Caco-2 cell system.

Abdomen↗
PubMed1996

Intestinal absorption studies on peptide mimetic alpha-methyldopa prodrugs.

Two dipeptide mimetic prodrugs, 1 and 2, and two tripeptide mimetic prodrugs, 3 and 4, of L-alpha-methyldopa were evaluated for intestinal absorption by in-situ single pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (Pm* = 2.27) as compared with that of alpha-methyldopa (Pm* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of K(m) (0.06 +/- 0.13 mM) and a high value of Vmax/K(m)(36.38 nmol (mg protein)-1/30s mM-1) at a low concentration range and a linear uptake at high concentrations with Kd = 0.14 +/- 0.02 mM. Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1. The uptake of compounds 1 and 4 was significantly inhibited by dipeptides L-Gly-L-Pro and L-Gly-L-Phe, and cephradine, a beta-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H(+)-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of alpha-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, D-phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.

Animals↗
PubMed2004

Intestinal absorption and hepatic extraction of propranolol and metoprolol in rats with bilateral ureteral ligation.

To investigate the mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats, the intestinal absorption and hepatic extraction of propranolol and metoprolol were evaluated. The initial absorption rate of these drugs after intra-intestinal administration was only slightly increased in the BUL rats, whereas the blood drug concentration in these rats was higher than that in control rats. The blood propranolol and metoprolol concentrations during intra-portal infusion in the BUL rat were significantly higher than that in the control rat. In the presence of NADPH, the intrinsic metabolic activity of metoprolol in hepatic microsomes was not altered by BUL. On the other hand, the NADPH generation rate in the hepatic cytosol in the BUL group was lower than that in the control group. These results indicate that the absorption rate-dependent decrease in hepatic first-pass clearance of propranolol and metoprolol due to saturation kinetics is marginal, and that the hepatic metabolic activity and extraction of the drugs is significantly decreased in BUL rats probably due to the reduced NADPH generation rate in the liver.

Adrenergic beta-Antagonists↗
PubMed1998

Intestinal absorption of nutrients is not influenced by soy fiber and does not differ between oligomeric and polymeric enteral diets.

Enteric feeding is often associated with diarrhea. To avoid this side effect, isoosmotic and fiber-supplemented enteral diets are recommended. The aims of this study were to determine whether supplementing enteral diets with soy fiber influences nutrient absorption and whether in enteric feeding absorption of nutrients and water fluxes differ between hyperosmotic oligomeric and isoosmotic polymeric diets. In mini pigs intestinal absorption and water fluxes were measured by perfusing a 150-cm length of jejunum. Six noncommercial iso- and hyperosmotic oligomeric and polymeric diets and six commercial polymeric diets, either fiber-free or supplemented with soy fiber, were used. Pancreatic enzymes were infused concomitantly with the polymeric diets. The absorption of nutrients and energy did not differ between oligomeric and polymeric diets. Oligomeric diets of high energy density produced a pronounced secretion of water. Despite lower initial osmolality, polymeric diets produced a similar secretion of water due to rapid pancreatic hydrolysis. Supplementing diets with largely insoluble soy fiber increased viscosity only between 4.6 and 14.5 mPa x sec. Soy fiber did not influence absorption of nutrients and energy and had also no effects on luminal transit and flow rate. The lack of effects was not due to dilution of chyme by intestinal secretion of water because no differences existed between isoosmotic and hyperosmotic oligomeric diets. In conclusion, supplementing enteral diets with soy fiber does not impair the absorption of nutrients. Enteric feeding with isoosmotic polymeric diets provides no advantage compared with hyperosmotic oligomeric diets with respect to absorption of nutrients and secretion of water.

Animals↗
PubMedDate not supplied

Using general regression and probabilistic neural networks to predict human intestinal absorption with topological descriptors derived from two-dimensional chemical structures.

The objective of this study was to develop rapid and reliable methods to predict the percent human intestinal absorption (%HIA) of compounds based on their 2D descriptors. The analyzed data set included 86 drug and drug-like molecules and was the same as that studied by Wessel and co-workers. Instead of using three-dimensional descriptors such as polar surface area, which require lengthy computations, we employed only two-dimensional topological descriptors derived from information about the two-dimensional structure of molecules. The %HIA values were modeled using a general regression neural network (GRNN) and a probabilistic neural network (PNN), variants of normalized radial basis function networks. Both networks performed well to model the %HIA values. The root-mean square (rms) error was 22.8 %HIA unit for the external prediction set for a GRNN model, and 80% of the external prediction set was correctly classified for a PNN model, indicating the potential of our approach to estimate the %HIA values for a large set of compounds as virtual libraries.

Humans↗
PubMed1978

Effect of 25-hydroxy-vitamin D3 on intestinal absorption of calcium in normal man and patients with renal failure.

The effects of short-term treatment with 25-hydroxy-vitamin D3 (25(OH)D3) on intestinal absorption of 47Ca were examined in 18 studies of normal subjects and 16 studies of patients with advanced renal failure. Doses of 25(OH)D3 were 20, 100, 500, or 1000 microgram/day given orally for 7--10 days. There was an increase in 47Ca absorption and urinary calcium in normal subjects receiving 20 microgram/day, while doses of 500 or 1000 microgram/day were required to augment 47Ca absorption in renal failure patients. During treatment, plasma levels of 25(OH)D increased to similar levels in both normal and uremic subjects. A comparison of the dose-response curves found 25(OH)D3 to be 1/125 as potent as 1,25-(OH)2D3 in the normal subjects and 1/400 as potent as 1,25(OH)2D3 in patients with chronic renal failure. Thus, pharmacologic doses of 25(OH)D3 are active in both normal and uremic patients, although relatively greater quantities are necessary in uremia. This difference in relative potency of 1,25(OH)2D3 and 25(OH)D3 may be explained by some conversion of 25(OH)D3 to 1,25(OH)2D3 in normal compared to uremic subjects, while 25(OH)D3 may act in large part via mass action in uremic patients.

Calcium↗
PubMed2006

Effect of the co-occurring components from green tea on the intestinal absorption and disposition of green tea polyphenols in Caco-2 monolayer model.

This study aimed to investigate the effect of co-occurring components from green tea on the intestinal absorption and disposition of green tea polyphenols (GTPs) using the Caco-2 cell monolayer model. The absorption and secretion transport of the four GTPs, in the form of individual pure compounds, pure compound mixtures and green tea extract, were studied in the Caco-2 cell model. Four GTPs and their metabolites were analysed by HPLC/MS and HPLC coupled with electrochemical detector. The apparent permeability coefficients (P(app)) of each compound, as well as the metabolites (mainly sulfation and methylation conjugates) generated, were compared for the different dosing formulations utilized. The results showed that the absorption transport of the four GTPs in different dosing formulations was similar. However, the secretion transport profiles of (-)-epicatechin (EC), (-)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG) were altered when the GTP mixture was administered. It was suggested that transporter competition resulting in reduced efflux of EC, as well as metabolic competition resulting in reduced formation of EGC sulfate and methylated EGC sulfate, might be involved during the secretion transport of GTP mixture.

Biological Transport↗