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PubMed1994

Intestinal absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue. I. Possible factors for the low oral bioavailability in rats.

Absorption of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, from the gastrointestinal (GI) tract was evaluated. The bioavailability of this compound after oral administration was considerably poor in rats. Studies were undertaken to elucidate the mechanisms for this low oral bioavailability of azetirelin. The plasma azetirelin levels following intravenous and hepatoportal vein injection were virtually identical over the dose range of 0.02-0.1 mg/kg, indicating a minor contribution of the hepatic first-pass metabolism of this drug. Azetirelin was stable against peptide hydrolases both in luminal fluid and intestinal mucosal homogenates, whereas its degradation occurred when incubated with cecal contents under an anaerobic condition. In addition, complete degradation of azetirelin during the GI transit was disclosed by analyzing the fecal sample collected after oral administration of [14C]azetirelin. These results suggested that gut bacteria may be responsible for the hydrolysis of azetirelin in the GI tract. The low intestinal permeability of azetirelin was revealed by a modified everted gut experiment in various segments of the rat intestine. The poor membrane transport characteristics of azetirelin may be due to its high hydrophilicity. From these results, it was suggested that the insufficient oral bioavailability of azetirelin may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity, and also to the degradation of the peptide by intestinal microflora.

Administration, Oral↗
PubMed1975

The effects of phytate on intestinal absorption and secretion of zinc, and whole-body retention of Zn, copper, iron and manganese in rats.

1. The inclusion of phytate (10 g/kg) in a purified diet containing zinc (15 mg/kg) fed to young male rats significantly reduced growth rate and food intake, and promoted a cyclic pattern of food intake characteristic of an uncomplicated Zn deficiency. The decreased growth rate could be accounted for by the reduced food consumption. 2. Rats maintained on a Zn-deficient diet (0.5 mg Zn/kg) were found to have a cyclic pattern of food intake and a very slight weight gain. The addition of phytate (10 g/kg) to the Zn-deficient diet promoted a net loss of mean body-weight. 3. Rats maintained on the Zn-supplemented diet containing phytate excreted significantly more Zn in their faeces than either pair-fed or ad lib.-fed control rats. Rats given the Zn-deficient diet supplemented with phytate excreted more Zn in their faeces than Zn-deficient control rats. 4. Dietary phytate significantly reduced the average daily accumulation (mug/d) and whole-body retention (relative to dietary intake) of iron, copper, manganese and Zn, whether or not the diet was supplemented with Zn. 5. The addition of phytate to the lumen fluid of ligated loops of rat duodenum maintained in situ significantly inhibited 65Zn absorption, compared with the control systems without added phytate. 6. Other studies using ligated duodenal and ileal loops indicated that Zn is secreted into the gut lumen and approximately one-third of this is normally reabsorbed. Recycling of endogenous Zn may be a significant process in the over-all body economy of this trace element. 7. The absorption of 65Zn added to the diet was significantly reduced by dietary phytate. Dietary phytate also reduced the biological half-life of body 65Zn from 61 to 211 h post-administration, possibly by inhibiting reabsorption of endogenous 65Zn and thus promoting a more rapid loss from the body.

Animals↗
PubMed1977

Intestinal absorption of glycine and glycyl-L-proline in the rat.

1. Absorption of [3H]glycine and [14C]-glycyl-L-proline at concentrations between 0-5 and 4 mmol/l was studied by perfusion in vivo of rat jejunal and ileal segments. Absorption was defined as net removal of radioisotope from the perfusate. Radioactivity assays and amino acid analyses were performed on perfusates and on mucosal tissue samples obtained from the perfused segments. 2. At the concentrations studied, absorption rates of glycine and glycylproline were proportional to concentration. Ileal rates were approximately 60% of jejunal rates. Glycylproline absorption was slightly faster than glycine absorption and was associated with the appearance in the perfusate of free glycine and proline in the ratio approximately 3:1. Intraluminal hydrolysis was insufficient to account for the amounts of free amino acids found and glycylproline hydrolase activity at the brush border is known to be minimal. 3. Glycylproline absorption apparently occurred by transport of the intact peptide followed by its intracellular hydrolysis. However, more than one-third of absorbed glycine and one-eighth of absorbed proline returned to the lumen as free amino acid. This reflux of glycine and proline was not proportional to their concentrations in the mucosa.

Animals↗
PubMed2002

Intestinal absorption of different types of folate in healthy subjects with an ileostomy.

Our knowledge on the absorption of folate is incomplete. The deconjugation process as a possible limiting factor in the absorption of folates was investigated. The study also attempted to validate the use of the area under the serum response curve (AUC) from food compared with folic acid as a proxy variable for food folate bioavailability. Folate absorption was determined in healthy ileostomy volunteers (n 11) using a single-dose short-term protocol. In a randomised crossover design, volunteers received spinach meals and a supplement. Based on analysis of test meals and ileostomy effluents, there was no difference in folate absorption between spinach with a mono-:polyglutamate ratio 40:60 and the same spinach with a 100:0 ratio. The absolute absorption of spinach folate (79 %) calculated from the difference between folate intake and folate content of ileostomy effluents was approximately equal to the relative absorption (81 %) calculated from the AUC after consumption of spinach meals in relation to the AUC after consumption of the folic acid supplement. We conclude that the deconjugation process is not a limiting factor in the absorption of spinach folates. Comparison of AUC of food folate v. folic acid in a short-term protocol may be suitable for assessing food folate bioavailability.

Adult↗
PubMed1989

Intestinal absorption of L-ascorbic acid in rats with renal failure.

We studied L-ascorbic acid absorption in rats subjected to subtotal nephrectomy (renal failure (RF) group) and compared the results with those obtained in sham-operated normal animals and those pair-fed with their azotemic counterparts (PF group). In vivo recirculating perfusion and in vitro everted sac techniques were employed. The in vitro experiments were repeated substituting buffer within the serosal compartment with pooled sera from uremic and normal individuals. L-Ascorbic acid absorption in vivo in the RF group was significantly lower than those found in normal control and PF groups. In contrast, the in vitro mucosal to serosal transport was increased in the RF and PF groups when compared with the normal control group, suggesting increased permeability to L-ascorbic acid in the former groups. The disparity between in vivo and in vitro results in the RF animals is indicative of some inhibitory influence present in the intact uremic animals. However, experiments comparing the effect of uremic with normal sera on in vitro transport failed to reveal any suppressive effect of uremic chemical environment. In addition, serum ascorbic acid was reduced in PF and RF groups when compared with the normal control animals, thereby excluding elevated blood level as a cause of impaired absorption in intact animals with RF. In conclusion, in vivo jejunal absorption of L-ascorbic acid is impaired in rats with RF despite evidence of increased in vitro permeability. The latter appears to be mediated by reduced nutrient intake and weight loss. The inhibitory influence present in vivo could not be reproduced by incubation with uremic sera in vitro.

Animals↗
PubMed1984

Intestinal absorption and structure in iron deficient piglets.

Absorption of D xylose by iron deficient piglets from three litters was as rapid as in their iron treated littermates, except when they were affected by diarrhoea. The dry matter content of the faeces of iron deficient piglets was marginally decreased, but the fat content of the faeces was significantly increased in two tests out of four. Diarrhoea in iron deprived piglets was associated with a small decrease in dry matter content and a large increase in fat content of the dry matter of the faeces and in fat excreted per kg bodyweight. Frank villous atrophy was evident histologically in iron deficient piglets which had diarrhoea when they were killed. Morphometric analysis of small intestinal specimens showed a significant decrease in villous length, villus-to-crypt ratio and mucosal complexity among iron deficient piglets. Crypt depth was not reduced.

Animals↗
PubMed1988

Acute inhibition by ethanol of intestinal absorption of glucose and hepatic glycogen synthesis on glucose refeeding after starvation in the rat.

1. Intragastric administration of ethanol (75 mmol/kg body wt.) at 1 h before glucose refeeding of 24 h-starved rats inhibited hepatic glycogen deposition (by 69%) and synthesis (by approx. 70%), but was without significant effect on muscle glycogen deposition and synthesis. 2. Treatment of ethanol-administered rats with methylpyrazole (an inhibitor of alcohol dehydrogenase) did not significantly diminish the inhibitory effect of ethanol on hepatic glycogen deposition after glucose refeeding, suggesting that the inhibition was not dependent on ethanol metabolism. 3. Ethanol delayed and diminished intestinal glucose absorption, at least in part by delaying gastric emptying. 4. At a lower dose (10 mmol/kg body wt.), ethanol inhibited hepatic glycogen repletion and synthesis without compromising intestinal glucose absorption. Ethanol inhibited glycogen deposition (by 40%) in hepatocytes from starved rats provided with glucose + lactate + pyruvate as substrates, consistent with it having a direct effect to diminish hepatic glycogen synthesis by inhibition of gluconeogenic flux at a site(s) between phosphoenolpyruvate and triose phosphate in the pathway. 5. It is concluded that ethanol acutely impairs hepatic glycogen repletion by inhibition at at least two distinct sites, namely (a) intestinal glucose absorption and (b) hepatic gluconeogenic flux.

Animals↗
PubMed1990

Bioavailability and the mechanisms of intestinal absorption of iron from ferrous ascorbate and ferric polymaltose in experimental animals.

The comparative bioavailability from matching quantities of iron in the form of ferrous ascorbate or ferric polymaltose was defined in rats. Studies were carried out in the intact animals under basal conditions and also when requirements for this metal were either increased or decreased by manipulating stores or erythropoietic activity. No significant difference was found in the total quantity of iron absorbed from either salt or complex under any of these circumstances, suggesting that the mucosal mechanism regulating the overall process was common to both. However, the rate of transfer from the lumen into portal blood was distinctive, reaching a maximum with salt at 30 min compared to 24 h for the complex. To explore the possibility that iron from the two sources was initially handled by different subcellular pathways, the radiolabeled compounds were instilled into loops of bowel that had been isolated between ligatures in vivo. Enterocytes were harvested and fractionated, and incorporation into ferritin and transferrin was determined using RIA. From salt, iron appeared rapidly in duodenal but not ileal ferritin, whereas mucosal transferrin increased under conditions of stimulated absorption, suggesting that this protein may act as a shuttle for the metal. In contrast, iron from polymaltose showed a cumulative incorporation into duodenal ferritin over time that correlated with iron absorption, defined by the appearance of radiolabel in the serum and in the carcass; a similar pattern was demonstrable in ileal mucosal cells. Conversely, binding of iron to transferrin was minimal. No iron polymaltose was found within the mucosal cells. It is suggested that the low rate of iron transfer from this ferric complex may reflect its extracellular breakdown in the lumen of the gastrointestinal tract.

Anemia, Hemolytic↗
PubMed1979

The intestinal absorption and excretion of 14C drotaverin in rats.

The absorption and biliary excretion of drotaverin/a papaverine analogue/were studied in rats. In vivo loop technique was used. The absorption of the compounds from the jejunum was found to be rapid and the activity injected into the duodenal sac to disappear only when the common bile duct was ligated. An appreciable activity was detected in the bile collected by cannulation following both i.v. (67%) or per os (31%) administration. Considerable activity was excreted with the bile even 24 hours after drug administration. A partial entero-hepatic cycle for the drotaverin metabolites is suggested.

Animals↗
PubMed1975

[In vitro intestinal absorption of sugars in the rat. Changes in concentrations of adenine nucleotides and inorganic phosphate in mucosa].

The absorption of three sugars by the rat gut: glucose, fructose and galactose, was studied in vitro' with a jejunal everted loop technique. The concentrations of the sugars in the serosal medium and in the mucosa cells were measured at given times, as well as the concentrations of ATP, ADP, AMP and inorganic P (Pi) in the mucosa cells. The time course of these concentrations was analyzed with the aid of polynomial regression, using the least squares method.

Adenine Nucleotides↗
PubMed1991

Intestinal absorption of drugs. The influence of mixed micelles on on the disappearance kinetics of drugs from the small intestine of the rat.

The solubilization of the hydrophilic drugs paracetamol and theophylline, and the lipophilic drugs dantrolene, griseofulvin and ketoconazole has been determined in mixed micellar aqueous dispersions composed of 10 mM taurocholate + 5 mM oleic acid. The solubilization of dantrolene and paracetamol has also been determined in aqueous (mixed) micellar dispersions of 1 g L-1 lysophosphatidyl-choline (LPC), or taurocholate/LPC. The influence of these (mixed) micelles on the absorption of the model drugs from solution was studied in the rat chronically isolated internal loop. Absorption kinetics of the drugs were evaluated on the basis of the disappearance rate of the drug dissolved in the perfusion medium in this loop. Absorption experiments with taurocholate/oleic acid in the perfusate resulted in a reduction of the disappearance rate for the lipophilic drugs and the hydrophilic drug theophylline. This could partly be ascribed to the decreased fraction of drug free in solution as a result of its micellar solubilization for dantrolene, griseofulvin and ketoconazole, but the decrease in the disappearance rate of theophylline was unexpected. Taurocholate/oleic acid, LPC and taurocholate/LPC micelles had no effect on the disappearance of paracetamol. The disappearance rate of dantrolene in the presence of LPC alone was not altered, in spite of the decreased fraction of the drug free in solution owing to its micellar solubilization. In contrast, taurocholate/LPC micelles caused a reduction in the rate of disappearance of dantrolene, as expected according to the phase-separation model. In-vitro, taurocholate and taurocholate/LPC reduced the molecular cohesion of porcine intestinal mucus, whereas LPC alone did not exhibit an effect on the gel structure of mucus.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed2005

Luminal leptin induces rapid inhibition of active intestinal absorption of glucose mediated by sodium-glucose cotransporter 1.

The effect of leptin on glucose transport was studied in rat jejunal mucosa in Ussing chambers. Leptin was added in the luminal or the serosal compartment before the tissues were challenged with 1, 10, or 50 mmol/l glucose. In response to 10 mmol/l glucose, the increase in short-circuit current (DeltaIsc) reached 26.8 +/- 2.1 microA/cm(2). Luminal addition of leptin dramatically decreased glucose-induced Isc (90.5% for 10 nmol/l leptin). Inhibition was maximal after 5 min and dose dependent (IC(50) = 0.13 nM). Western blot analysis showed that rapid inhibition of glucose-induced Isc by leptin was associated with a parallel decrease in the abundance of sodium-glucose transporter-1 in brush border membranes. Inhibition by luminal leptin of DeltaIsc was prevented by inhibitor of conventional protein kinase C isoforms. Serosal addition of leptin did not decrease glucose-induced Isc within 5 min and reached maximum after 10 min. The effect of leptin from serosal side was blocked by cholecystokinin (CCK) receptor-2 receptor antagonist YM022. Altogether, these data demonstrate that luminal leptin induces rapid inhibition of glucose entry into enterocyte. The slower action of leptin on the serosal side of mucosa seems indirect and is likely mediated by endogenous CCK. They demonstrate that gut leptin is a major regulator of rapid intestinal glucose transport.

Acetophenones↗
PubMed1992

The role of insulin in the intestinal absorption of glucose in the rat.

1. Acute pre-treatment with either mannoheptulose or streptozotocin--both compounds acting as powerful suppressors of insulin secretion--caused a significant decrease on the in vivo rate of intestinal glucose absorption following an intragastric [U-14C]glucose administration. 2. Mannoheptulose treatment also lowered the rate of whole-body oxidation of the administered tracer. 3. Insulin had no effect on the metabolic fate of [U-14C]glucose by isolated enterocytes. 4. However, the rate of glucose uptake, measured by the oxidation of [1-14C]glucose to 14CO2 in the presence of phenazine methosulphate, was decreased by insulin at concentrations of 50-200 munits/ml. 5. In addition, the rate of transport of [U-14C]glucose by brush-border membrane vesicles was also inhibited by insulin at high concentrations (100-1000 munits/ml). 6. This indicated that insulin acts by inhibiting glucose transport in isolated in vitro preparations. 7. Acute pre-treatment with either mannoheptulose or streptozotocin caused a significant decrease in the rate of gastric emptying, measured as the distribution of [3H]insulin along the gastrointestinal tract, following an intragastric glucose load. 8. It is concluded that insulin secretion modulates intestinal glucose absorption in vivo by enhancing gastric emptying in spite of the inhibitory effects of glucose transport observed with in vitro preparations.

Animals↗