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Intestinal absorption and metabolism of homoursodeoxycholic acid in rats.

Intestinal absorption, hepatic biotransformation and intestinal bacterial modification of the C25 homolog of ursodeoxycholic acid, homoursodeoxycholic acid, and its glycine conjugate, glycohomoursodeoxycholic acid, were studied in rats. Homoursodeoxycholic acid, like ursodeoxycholic acid, was efficiently absorbed from the intestine and rapidly excreted into the bile. Most (greater than 95%) of the absorbed homoursodeoxycholic acid was found to undergo beta-oxidation to form two C23 bile acids, norursodeoxycholic acid and nor-beta-muricholic acid during passage through the liver. Bacterial modification of homoursodeoxycholic acid was very similar to that of ursodeoxycholic acid. In the rat intestinal tract, glycohomoursodexycholic acid was deconjugated to form unconjugated homoursodeoxycholic acid which was then 7 beta-dehydroxylated to form homolithocholic acid.

Animals↗

Intestinal absorption and metabolism of norcholic acid in rats.

Intestinal absorption and hepatic and intestinal bacterial biotransformations of norcholic acid, the C23 homologue of cholic acid, were studied in the rats. Norcholic acid, like cholic acid, was efficiently absorbed from the intestine and quickly secreted into the bile. Unlike the C24 bile acid, however, which is secreted by rat liver as its taurine conjugate, the C23 bile acid appeared in the bile predominantly as the unconjugated form. conjugated form. Bacterial modification of norcholic acid was similar to but less extensive than that of cholic acid. A considerable part of norcholic acid was left unchanged during its passage through the intestinal tract. A major bacterial metabolite of norcholic acid was the 7-dehydrogenation product, 7-ketonordeoxycholic acid, rather than the 7-dehydroxylation product, nordeoxycholic acid, though the reverse is true for cholic acid.

Animals↗

In situ intestinal absorption studies on low molecular weight heparin in rats using labrasol as absorption enhancer.

Oral absorption of low molecular weight heparin (LMWH) is limited by its molecular size and negative charge. Development of its oral formulations would allow outpatient treatment with LMWH and decrease the hospital expenses. Studies were aimed at evaluating Labrasol for improving intestinal absorption of LMWH. Formulations containing LMWH and Labrasol were administered to duodenum, jejunum, and ileum of the fasted rats. The doses of LMWH and Labrasol were 200 IU/kg and 50 mg/kg, respectively. Reversibility of absorption enhancing effect of Labrasol was assessed by administering LMWH to jejunum after 0.5 and 1 h of administration of Labrasol. The effect of different doses of Labrasol on LMWH absorption was studied by administering Labrasol at 50, 100, and 200 mg/kg doses. Administration of LMWH formulation tojejunum resulted in the highest plasma anti-Xa activity (0.50+/-0.03 IU/ml) compared to duodenum (0.19+/-0.03 IU/ml), and ileum (0.29 +/-0.06 IU/ml) and the anti-Xa levels were maintained above the therapeutic level for about 160 min. The absorption of LMWH was negligible when LMWH was administered at 0.5 and 1 h post-Labrasol administration. Increasing the dose of Labrasol has decreased the absorption of LMWH from jejunum. Labrasol increased the intestinal absorption of LMWH, and jejunum was found to be the best site of absorption. Intestinal membrane permeability changes induced by Labrasol were transient and reversible. Maintaining high drug concentration gradient across intestinal wall is important to obtain increased intestinal LMWH absorption.

Animals↗

Intestinal absorption of choline in rats.

The intestinal absorption of choline, an endogenous quaternary ammonium, from the rat jejunum has been investigated with an in situ ligated loop method and an in vitro everted sac method. Choline was absorbed rapidly from the ligated jejunum and structural analogs inhibited choline absorption competitively. In in vitro experiments, choline was transported from the mucosal fluid to the intracellular fluid against a concentration gradient and the rate of tissue uptake was highly affected by incubation temperature, aerobic condition and the presence of a metabolic inhibitor, 2,4-dinitrophenol. The tissue accumulation of choline was saturable at concentrations below 100 microM and, above this concentration the uptake ratio of choline (medium to tissue) was almost constant. One mM hemicholinium-3, which is well known to inhibit choline uptake by neurons through the choline specific carrier, also significantly inhibited choline uptake, especially at concentrations of choline below 100 microM. The fact that the choline uptake is linear in the presence of hemicholinium-3 shows that choline is partially absorbed by passive diffusion. The difference between the total tissue accumulation and choline uptake by the passive diffusional pathway followed Michaelis-Menten kinetics and the apparent Kt of 47 microM and Vmax of 4.1 nmol/ml intracellular fluid/min were determined by an in vitro everted sac method. These findings suggested that, a lower concentrations, choline was absorbed from the rat intestine mainly by an active transport system.

Animals↗

Epinephrine is an enhancer of rat intestinal absorption.

Some physiological substances, including acetylcholine and nitric oxide, are useful candidates for stimulation of intestinal absorption of drugs. In the present study, we elucidated the ability of epinephrine (Epi) to stimulate the intestinal absorption of drugs. We evaluated the ability of Epi to enhance absorption of macromolecules using dextran (Mw 4000 Da), which is poorly absorbed from the intestine, as a model compound in situ in a closed loop of the rat jejunum. Treatment of the jejunum with Epi resulted in significant increase in absorption of dextran in a dose-dependent fashion. The area under the curve (AUC) from 0 to 4 h in the Epi-treated jejunum was 13-fold higher than that in the vehicle-treated jejunum. The absorption-enhancing activity of Epi was 40-fold higher than that of caprate, a clinically used absorption-enhancer of drugs. In the experimental conditions used in this study, histological injury of the mucosa and perturbation of the mucosal membrane were not observed in the Epi-treated jejunum. Treatment with an antagonist of alpha-adrenergic receptors attenuated the stimulation of intestinal absorption by Epi, and treatment with an agonist of alpha-adrenergic receptors resulted in enhancement of intestinal absorption. While an antagonist of beta-adrenergic receptors enhanced the absorption-enhancing effect of Epi, an agonist of beta-adrenergic receptors stimulated intestinal absorption. These results indicate that stimulation of adrenergic receptors may be a novel strategy for intestinal absorption of drugs.

Animals↗

Enhancing effects of monohexanoin and two other medium-chain glyceride vehicles on intestinal absorption of desmopressin (dDAVP).

The intestinal absorption enhancement of the nonapeptide [Mpa1,D-Arg8]vasopressin (dDAVP) by medium-chain glyceride vehicles was studied using an in vivo rat model. Rats were gavaged with dDAVP formulated with three different lipid vehicles: (1) monohexanoin, (2) mixed monoglycerides, diglycerides and triglycerides of hexanoic acid and (3) monoglycerides, diglycerides and triglycerides of octanoic and decanoic acids, and with saline as control. The marker absorption into blood and urine was followed for 24 hr. All lipid vehicles enhanced the oral bioavailability of dDAVP, but monohexanoin gave the highest increase, approximately 10 times that of control. In contrast to dDAVP, the stable and more lipophilic nonapeptide analog [Mpa1,D-Tyr(ethyl)2,Val4,D-Arg8]oxytocin did not show increased urine recovery when formulated with monohexanoin. A 2-fold increase in urine recovery of the inert low-molecular-weight marker [51Cr]EDTA was observed when formulated with monohexanoin. With use of the fluorescent marker Evans blue formulated with monohexanoin, an elevated accumulation of Evans blue in the mucus layer was observed after incubation in in situ loops. No mucosal damage after lipid vehicle gavage was observed by light microscopic evaluation. Medium-chain glycerides functioned well as oral absorption enhancers of the model peptide dDAVP, and monohexanoin showed the highest enhancement capacity. The mechanisms of this enhancement appear to be related to a protection against luminal dDAVP degradation, mucoadhesive properties of the vehicle and, possibly, an altered epithelial absorption pathway.

Animals↗

Incomplete intestinal absorption of fructose.

Intestinal D-fructose absorption in 31 children was investigated using measurements of breath hydrogen. Twenty five children had no abdominal symptoms and six had functional bowel disorders. After ingestion of fructose (2 g/kg bodyweight), 22 children (71%) showed a breath hydrogen increase of more than 10 ppm over basal values, indicating incomplete absorption: the increase averaged 53 ppm, range 12 to 250 ppm. Four of these children experienced abdominal symptoms. Three of the six children with bowel disorders showed incomplete absorption. Seven children were tested again with an equal amount of glucose, and in three of them also of galactose, added to the fructose. The mean maximum breath hydrogen increases were 5 and 10 ppm, respectively, compared with 103 ppm after fructose alone. In one boy several tests were performed with various sugars; fructose was the only sugar incompletely absorbed, and the effect of glucose on fructose absorption was shown to be dependent on the amount added. It is concluded that children have a limited absorptive capacity for fructose. We speculate that the enhancing effect of glucose and galactose on fructose absorption may be due to activation of the fructose carrier. Apple juice in particular contains fructose in excess of glucose and could lead to abdominal symptoms in susceptible children.

Adolescent↗

Effects of vasoactive intestinal polypeptide on intestinal absorption and blood flow.

1. Intestinal absorption and blood flow in anaesthetized dogs was determined after I.V. infusion of vasoactive intestinal polypeptide (VIP) (1.75-175 ng/min) to determine the contribution of the cardiovascular changes to transport. 2. 22Na and 3H2O were utilized to determine the unidirectional fluxes of Na and H2O from saline perfused through the ileal lumen and the clearances of 3H2O were used to determine total and absorptive site blood flow. 3. Net Na and H2O absorption were reversed to secretion by VIP at 175 ng/min due to a significant decrease in unidirectional absorptive fluxes and smaller increases in secretory fluxes. 4. Arterial pressure and absorptive site blood flow were reduced in proportion to the changes in Na and H2O fluxes. 5. Total and absorptive site blood flow decreased and the blood flow resistances increased. 6. Prior treatment with guanethidine to suppress sympathetic effects did not greatly affect the responses to VIP. Prior treatment with atropine to suppress cholinergic effects inhibited most of the effects of VIP. 7. Absorptive site blood flow was linearly related to absorptive fluxes of Na and H2O but with different slopes for results from atropinized dogs as compared to those from dogs given VIP alone or VIP plus guanethidine. 8. It was concluded that VIP reduces gut absorption through a generalized cardiovascular effect and also through a mechanism which depends on the release of ACh by the gut.

Animals↗

Intestinal absorption of fluoride preparations.

Gastric intestinal absorption of five different preparations of sodium fluoride was measured by means of ten hour urinary excretion. Best absorption was by nonenteric coated sodium fluoride. All three enteric coated preparations showed poorer absorption, with marked individual variations. Florical, the currently available preparation, showed better absorption than any enteric coated tablets and only slightly less than sodium fluoride alone. For active cochlear otospongiosis two capsules three times a day should be prescribed.

Administration, Oral↗

Restricted intestinal absorption of some beta-lactam antibiotics by an energy-dependent efflux system in rat intestine.

PURPOSE: The purpose of this study was to examine factors limiting the intestinal absorption of orally inactive beta-lactam antibiotics. METHODS: Permeation behaviors of various beta-lactam antibiotics across rat intestinal segments were evaluated in vitro using diffusion cells. RESULTS: Poorly absorbed beta-lactam antibiotics, like cephaloridine and cefoperazone, commonly exhibit greater serosal-to-mucosal permeation than mucosal-to-serosal permeation, while cephalexin permeation was greater in the mucosal-to-serosal direction. In the absence of D-glucose, secretory-oriented permeation of cephaloridine and cefoperazone disappeared. Addition of sodium azide into an experimental buffer including D-glucose significantly and selectively enhanced mucosal-to-serosal permeation of cephaloridine and cefoperazone. Although benzylpenicillin, ampicillin, and amoxicillin all showed secretory-oriented permeation, the tendency to permeation was greatest with benzylpenicillin and least with amoxicillin. Probenecid stimulated mucosal-to-serosal permeation of cephaloridine, but verapamil and p-aminohippuric acid had no significant effect on it. CONCLUSIONS: It has been suggested that mechanisms which induce secretory-oriented permeation of orally inactive beta-lactam antibiotics are factors limiting intestinal absorption of such antibiotics. This energy-demanding efflux system was distinct from P-glycoprotein-mediated transport. A free alpha-amino group in the molecule is an important factor for reducing an affinity with the efflux system.

Animals↗

Preference of Peyer's patches to jejunal epithelium for intestinal absorption of oligopeptides, tyrosylglycylglycine and D-kyotorphin.

The intestinal absorption of oligopeptides, peptidase-degradable tyrosylglycylglycine (TGG) and peptidase-resistant L-tyrosyl-D-arginine (D-kyotorphin, D-KTP) across Peyer's patches (PP) in rabbit intestine were studied using an Ussing-type chamber and in situ closed perfusion methods. The clearance for the serosal appearance of intact TGG across PP by the Ussing-type chamber method was a little higher than that across the jejunal epithelium (JE). Meanwhile, the in situ closed perfusion experiment showed that the clearance for the plasma appearance of intact TGG across PP was about 10 times that of JE. Furthermore, it was shown that the clearance for the plasma appearance of D-KTP in PP was about twice that in JE by the in situ closed perfusion method, indicating that the membrane permeability of PP was higher than that of JE. Therefore, these results indicate that PP had less metabolic peptidase activity than JE, and that the PP was a suitable site for the intestinal absorption of oligopeptides, especially peptidase-degradable peptides.

Animals↗

Age-dependent alterations of intestinal absorption. II. A clinical study using a modified D-xylose absorption test.

With advancing age functional and morphological changes take place within the intestinal tract. The age-dependency of intestinal absorption has been studied using a D-xylose absorption test. The absorption rate (constant k12), the time of appearance of the relative maximum of the D-xylose concentrations in the blood serum after oral administration (time tm), and the extent of the relative absorption in the small intestine as a function of time RA(t) were determined by graphic-mathematical evaluation of the blood level kinetics of D-xylose after oral and intravenous administration. Within the age range of 3 to 96 yr, it has been proven that a slowing down of intestinal absorption occurs with advancing age. By prolonging the period during which the food components are absorbed in the small intestine (shift of tm towards the absorption processes take place at a slower rate. Absorption disorders in old age are due to morbidity and not, sui generis, to involution.

Adolescent↗

Epithelial cell proliferation and intestinal absorptive function during starvation and refeeding in the rat.

1. Intestinal epithelial cell production and intestinal absorption were measured in fed, starved and refed rats. 2. Four days' starvation significantly decreased the crypt cell production rate (CCPR), absorption, small intestinal length and crypt cell population. 3. There was an immediate increase in absorption 1 day after refeeding, which preceded a slower increase in CCPR. The absorption rate then decreased progressively after refeeding, and was significantly lower than control levels 1 week after refeeding. The CCPR, however, increased more gradually, reaching control levels after 2 days and then 'overshooting' control values. 4. There was no significant change in the crypt cell population immediately after refeeding; thus we propose that the initial increase in absorption on refeeding is either due to an accelerated maturation rate of the enterocytes or to the migration of enterocytes from the base of the villus to the functional zone. 5. The rapid recruitment of absorptive function appeared to be a 'one-off' event, the villus compartment then having to wait for increased cell production in the crypts to repopulate the villi.

Animals↗

Intestinal absorption of calcium in newborn piglets. Role of vitamin D.

The role of vitamin D for intestinal absorption of Ca was studied in neonatal piglets. Piglets of normal phenotype (heterozygotes) and piglets which suffered from pseudo-vitamin D deficiency rickets, type I, which were devoid of renal 25-cholecalciferol-1-hydroxylase were used for the experiments. Intestinal absorption of Ca was measured after an oral dose of 3-7 MBq 45CaCl2. Intestinal absorption of Ca was the same in heterozygotes and homozygotic rachitic piglets during the first 3-4 weeks of life. Ca absorption began to decline in rachitic piglets at the age of 4 weeks. In 8-week-old rachitic piglets intestinal Ca absorption was 50% of control piglets. Body weights of heterozygotes and rachitic piglets were the same at birth and no different weight gains were seen between the two groups during the first 4-5 weeks of life. No differences were observed during the first weeks of life in the concentrations of plasma Ca, inorganic-phosphate and alkaline-phosphatase activity between the groups. Hypocalcemia and hypophosphatemia developed in rachitic piglets between the 3rd and 5th weeks of life. Concentrations of 1,25-(OH)2D3 in plasma declined in heterozygote piglets from 130 +/- 26 to 88 +/- 19 pg/ml and in rachitic piglets from 67 +/- 37 to 23 +/- 11 pg/ml during the first 6 weeks. An intestinal nuclear 1,25-(OH)2D3 receptor was absent in neonatal piglets of both experimental groups. It is concluded that intestinal absorption of Ca in piglets during the first 2-4 weeks of life is independent of vitamin D.

Alkaline Phosphatase↗

Intestinal absorption of ursodeoxycholic acid in children and adolescents with inflammatory bowel disease.

BACKGROUND: Ursodeoxycholic acid absorption in the proximal intestine may be impaired in patients with inflammatory bowel disease. METHODS: We examined the intestinal absorption of ursodeoxycholic acid by the oral ursodeoxycholic acid tolerance test in 19 children and adolescents with inflammatory bowel disease at various stages, including 8 patients with unoperated Crohn's disease, 3 patients with ileal-resected Crohn's disease, 8 with ulcerative colitis, and 8 healthy control subjects. RESULTS: Ursodeoxycholic acid malabsorption was present in all patients with unoperated Crohn's disease in the first diagnosed active stage, in 3 of 5 patients in a relapsing active stage, and in 2 of 8 patients in remission. Ursodeoxycholic acid absorption was significantly lower in patients in the first diagnosed active stage than in the healthy controls (p < 0.01) or in patients in remission (p < 0.01). There was no significant difference between healthy controls and the patients in a relapsing active stage or in remission. Ursodeoxycholic acid absorption was abnormal during the first postoperative month in patients with ileal-resected Crohn's disease, but normalized over time. Malabsorption of ursodeoxycholic acid was not observed in any patients with ulcerative colitis. CONCLUSIONS: These findings suggest that absorption of ursodeoxycholic acid in the proximal intestine is impaired in patients with Crohn's disease and that the oral ursodeoxycholic acid tolerance test is a convenient and useful means of evaluating the absorption of bile acid in the proximal intestine in pediatric patients with ileal or ileocolic Crohn's disease.

Adolescent↗

Effects of ethanol on intestinal absorption of drugs. I. In situ studies with ciprofloxacin analogs in normal and chronic alcohol-fed rats.

The effect of chronic alcohol intake on the intestinal absorption of seven compounds belonging to a homologous series (ciprofloxacin derivatives) was evaluated using an in situ rat gut technique that measures the intrinsic absorption rates of the compounds both in control and chronic alcohol-fed rats. For chronic alcohol treatment, the animals were fed a liquid diet containing ethanol (36% of calories), whereas an isocaloric diet was given to the pair-fed control animals. The biophysical absorption model, relating the intestinal absorption rate constants and partition indexes of the tested compounds, was then established either for control or alcohol-fed animals. Differences were analyzed and tentatively interpreted on the basis of general diffusion principles. Results revealed that, in chronic alcohol-fed animals, hydrophilic homologs are absorbed at a significantly faster rate than in control ones, whereas lipophilic homologs do not change their absorption rate relative to controls. Results demonstrate that the bulk polarity of the microvillous lipoidal membrane is enhanced by chronic ethanol intake, whereas basic features of the aqueous boundary layer are not altered. These observations suggest that the physicochemical properties of the compounds are an important factor in explaining the influence of chronic alcohol intake on passive intestinal absorption of xenobiotics. The possible practical implications of our results are discussed from a speculative view-point.

Alcoholism↗

Lead: intestinal absorption and bone mobilization during lactation.

The aim of this study was to examine lead (Pb) intestinal absorption, its mobilization and redistribution during lactation in rats chronically exposed to lead. Lead and calcium (Ca) concentrations were measured in blood, milk, femurs, liver and kidney samples obtained from pregnant and lactating mother rats which were subjected to different schedules of exposure to Pb: 158 days before and during lactation (group A), 144 days before lactation (group B) and 14 days only during lactation (group C). Results were compared to those of non-pregnant but Pb-exposed matched rats and non-exposed control rats. In groups A and B during lactation, Pb in blood (PbB), liver and kidney increased while Pb in bone decreased. Since there was not an external source of Pb in group B during lactation, the results indicate resorption of Pb in bone as the main source of Pb in the organism. In group A, there was an additional increase of PbB when compared to group B as a result of Pb intestinal absorption. In group C a significant increase in PbB due to intestinal absorption and deposit in bone was found when compared to non-pregnant 144 days old rats, suggesting that the three processes intestinal absorption, bone resorption and bone absorption were taking place. These data indicate that Pb stored in bone as a result of prior maternal exposure, should be considered as a major source of self intoxication and of Pb in milk available to suckling pups.

Administration, Oral↗

Differential effect of steroids and chloroquine on the intestinal absorption of aluminium and calcium.

In rats with normal renal function the intestinal absorption of aluminium appears to be partly vitamin D dependent. To further characterise the similarities between the absorption of aluminium and calcium we investigated the effects of dihydroxylated vitamin D metabolites, prednisolone, and chloroquine (CQ) in Sprague-Dawley rats with normal or reduced renal function. The latter agents interfere with lysosomal functions and have been reported to reduce the intestinal absorption of calcium, whereas vitamin D metabolites may stimulate the absorption of both aluminium and calcium. To assess the intestinal absorption of aluminium we monitored urinary aluminium excretion and serum aluminium concentrations following an oral load of 410 mumol aluminium. Calcium absorption was calculated from the differences between an orally administered dose of 45calcium and faecal excretion. In vitamin-D-deficient rats cholecalciferol and calcitriol augmented urinary aluminium excretion to a similar degree subsequent to an oral load whereas 24R,25(OH)2D3 was without an apparent effect. In vitamin-D-replete rats with normal renal function CQ (225 mg/kg i.p.; 3 days) as well as prednisolone (25 mg/kg; 7 days) significantly reduced calcium absorption (% dose) (CQ: 39 +/- 5%, prednisolone: 42 +/- 3%, control: 58 +/- 11%). In contrast neither drug reduced urinary aluminium excretion (CQ: 519 +/- 92, prednisolone: 494 +/- 137, control: 469 +/- 187 nmol/5 days) or the postload increase in serum aluminium following oral exposure. When aluminium was administered intravenously recovery of aluminium was comparable between treatment groups and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗