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Improvement of intestinal absorption of P-glycoprotein substrate by D-tartaric acid.

The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Distribution kinetics and intestinal absorption of practolol in the rat.

1. After intravenous injection of practolol the blood concentration-time curve is fitted by a bi-exponential function. A two compartment open system model is therefore a minimal requirement in order to describe adequately the distribution of the drug in the body.2. The parameters of the two compartment model for practolol were determined. The mean values for the ;fast disposition' half life and the ;slow disposition' half life were 0.5 min and 13.3 min, respectively.3. The rate constants of distribution and elimination were similar in different animals. The volume of the central compartment was related to the weight of the animal.4. The absorption of practolol from an intestinal site was measured by its appearance in the blood. The rate constant for this process was estimated to be 0.03 min(-1).

Acetanilides↗

Intestinal absorption of food antigens in coeliac disease.

Serum concentrations of ovalbumin, beta-lactoglobulin, and antigen-antibody complexes were measured after jejunal administration of milk and raw egg in 6 children with active coeliac disease and in 4 controls. The results did not support the hypothesis of a generalised increase in absorption of antigens from the intestinal lumen in coeliac disease.

Antigen-Antibody Complex↗

Changes in intestinal absorption of nutrients and brush border glycoproteins after total parenteral nutrition in rats.

The effect of total parenteral nutrition on nutrients absorption and glycoprotein changes of brush border membrane was examined in rat small intestine. In total parenteral nutrition rats, a marked decrease in activity of brush border enzymes was observed mainly in the proximal and middle segments of the intestine. Galactose perfusion of jejunal segment showed that hexose absorption was significantly inhibited, while intestinal absorption of glycine or dipeptide, glycylglycine was not significantly affected by total parenteral nutrition treatment. When brush border membrane glycoprotein profile was examined by [3H]-glucosamine or [3H]-fucose incorporation into jejunal loops, significant changes were observed in the glycoprotein pattern of brush border membrane especially in the high molecular weight range over 120 kDa after total parenteral nutrition treatment, suggesting strong dependency of glycoprotein synthesis on luminal substances. Molecular weight of sucrase isomaltase in brush border membrane detected by specific antibody showed no significant difference, however, in total parenteral nutrition and control rats. Also, molecular weight of specific sodium glucose cotransporter of intestinal brush border membrane detected by selective photoaffinity labelling was not altered in total parenteral nutrition rats. It may be that prolonged absence of oral food intake may produce significant biochemical changes in brush border membrane glycoprotein and absorptive capacity of small intestine, but these changes were not observed in all brush border membrane glycoproteins.

Animals↗

Iron dissociates from the NaFeEDTA complex prior to or during intestinal absorption in rats.

Sodium iron ethylenediaminetetraacetate (NaFeEDTA) has superior iron bioavailability especially in foods containing iron absorption inhibitors. However, mechanisms involved in the absorption and subsequent partitioning of iron complexed with EDTA are poorly understood. Our objectives were to compare retention and tissue distribution of iron administered to rats either as FeSO4 or NaFeEDTA, either orally (OR) or subcutaneously (SC). Weanling rats were fed semipurified diets supplemented with either FeSO4 or NaFeEDTA for 7 days. They were then given a meal containing 59Fe-labeled FeSO4 or NaFeEDTA, or they were injected SC with these two forms of radiolabeled Fe. 59Fe retention was measured by whole body counting. Urine was collected and counted at 24 h intervals throughout the counting period. Tissue samples were analyzed for nonheme iron and 59Fe activity. Absorption of iron from FeSO4 or NaFeEDTA was similar (57.7 and 53.4%, respectively). Seventy-seven percent of the injected Na59FeEDTA was excreted in the urine within 24 h, whereas only 0.5, 0.8, and 1.4% of the injected 59FeSO4, oral 59FeSO4, and oral Na59FeEDTA, respectively, was excreted in the urine. The nonheme iron content was lower in the liver and spleen, by 56.8 and 28.4%, respectively, among rats consuming the NaFeEDTA diet as compared to rats fed FeSO4. We conclude that iron is dissociated from EDTA prior to or during intestinal absorption and that some fraction of the dissociated EDTA is absorbed separately from the iron.

Animals↗

Intestinal absorption of dietary carotenoids.

The assessment of carotenoid bioavailability has long been hampered by the limited knowledge of their absorption mechanisms. However, recent reports have elucidated important aspects of carotenoid digestion and absorption. Disruption of food matrix and increasing amounts of fat seem to enhance the absorption of carotenes to a larger extent than that of xanthophylls. Comparing different carotenoid species, xanthophylls seem to be more easily released from the food matrix and more efficiently micellized than the carotenes. On the other hand, carotenes are more efficiently taken up by the enterocytes. However, carotenoid emulsification and micellization steps are largely affected by the food matrix and dietary components, being the main determinant of carotenoid bioavailability from foodstuffs. Although the intestinal uptake of carotenoids has been thought to occur by simple diffusion, recent studies reported the existence of receptor-mediated transport of carotenoids in enterocytes. Comparisons between the intestinal absorption of a wide array of carotenoids would be useful to elucidate the absorption mechanism of each carotenoid species, in view of the recent indications that intestinal carotenoid uptake may involve the scavenger receptor class B type I and possibly other epithelial transporters. The unraveling of the whole mechanism underlying the absorption of carotenoids will be the challenge for future studies.

Animals↗

Intestinal absorption and 25-hydroxylation of vitamin D in patients with primary biliary cirrhosis.

The absorption, metabolism, and excretion of vitamin D3 was studied in eight women with an established diagnosis of primary biliary cirrhosis (PBC), and the results were compared with those obtained from eight healthy women of a similar age. Four patients had hyperbilirubinemia, low serum calcium levels, and a reduced mineral content of the bone, whereas the other four were presymptomatic with respect to bone disease. Vitamin D absorption was studied after oral administration of tritiated vitamin D, and the appearance of serum radioactivity was recorded. After this, the liver 25-hydroxylation of vitamin D was studied by administering an intravenous dose of tritiated vitamin D and then chromatographing serum samples to determine the radioactivity of the 25-OH D fraction. All PBC patients had normal 25-hydroxylation capacity of the vitamin, and there was no difference in the urinary excretion of radioactivity. On the other hand, the intestinal absorption of vitamin D was severely impaired both in the symptomatic and asymptomatic patients. The absorption of the vitamin was negatively correlated to the amount of fecal fat, and the results suggest that low serum levels of 25-OH D in symptomatic PBC seem to be caused by the steatorrhea, whereas hepatic conversion of vitamin D into 25-OH D seems to be well preserved even in patients with hyperbilirubinemia and signs of osteomalacia. The absorption-metabolism test may be a valuable tool in the study of patients with cholestatic liver disease for determining the nature of the vitamin D deficiency and the logical form of substitution therapy.

Adult↗

Intestinal absorption of sodium and nitric oxide-dependent vasodilation interact to dominate resting vascular resistance.

The villi of the small intestine maintain a hypertonic interstitium at all times, and the submucosal glands constantly secrete ions and accompanying water into the lumen. Generation of the 400- to 600-mOsm interstitial fluid in the villus and secretion by glands may require a large expenditure of energy and, consequently, have major effects on intestinal vascular regulation to supply oxygen and nutrients. Blood flow and oxygen consumption were measured in the ileum of anesthetized rats during natural resting conditions with physiological sodium chloride in the bathing fluid and during isosmotic replacement of sodium chloride with mannitol. Microvascular pressures and blood flow were used to determine the changes in resistance of the major arterioles and the terminal vasculature. When mannitol replaced sodium chloride in contact with the villi, intestinal blood flow decreased to 58.6 +/- 2.8% of control, and oxygen consumption was 54.2 +/- 3.4% of control. Resistance of the major arterioles increased 101.7 +/- 9.9%, and that of the terminal vasculature increased 40.4 +/- 6.2%. The increased resistance appeared to be caused by suppression of a nitric oxide mechanism. Local application of 10(-4) mol/L NG-nitro-L-arginine methyl ester caused about the same reduction in flow and increases in regional vascular resistance as during replacement of sodium but did not alter the oxygen consumption. These data indicate that about half of the intestinal metabolic rate during natural resting conditions is devoted to sodium secretion/absorption. Large resistance vessels are dilated to maintain a high blood flow through release of nitric oxide. We propose that dilation of the terminal vasculature in the metabolically active tissues increased flow velocity sufficiently in the major resistance vessels to cause a flow-mediated release of nitric oxide.

Animals↗

The effect of saccharolactone on rat intestinal absorption of bilirubin in the presence of human breast milk.

Beta-glucuronidase hydrolyzes glucuronic acid from bilirubin glucuronides. The unconjugated bilirubin that results is more readily absorbed from the intestine. Human breast milk has significant beta-glucuronidase activity, and it has been suggested that the milk may play an etiologic role in the hyperbilirubinemia commonly seen in breast-fed infants. To test whether breast-milk can facilitate intestinal bilirubin absorption, pairs of rats were fitted with bile duct and duodenal catheters. One rat of each pair received an intraduodenal infusion of rat bile plus breast-milk; the other rat received a similar amount of bile and milk plus the beta-glucuronidase inhibitor saccharolactone. Rats receiving saccharolactone excreted significantly less bilirubin in their bile, suggesting that inhibition of beta-glucuronidase decreased intestinal absorption of bilirubin. These findings were not seen in similar experiments when saline was substituted for human breast-milk.

Animals↗

Permanent bile duct cannulation in the monkey. A model for studying intestinal absorption.

Our aim has been to obtain an experimental model where the test animal is subjected to the least amount of stress and restraint, and can serve for the repeated sampling of biliary excretion over a prolonged period of time. By using a special end-piece at the outer terminals of the two cannulas the monkeys could be given full freedom after experimentation. During the course of the study it was found that insertion of the cannula into the common bile duct led to the development of collateral pathways for passage of bile around the point of insertion. This adaption reaction for the restoration of a normal bile channel would seem to be characteristic of Rhesus monkeys, for we did not encounter it in similar experiments on dogs and minipigs. The experimental model described is intended to serve for the determination of intestinal absorption of compounds that are mainly excreted via the bile. Results with radioactive ergotamine are presented.

Animals↗

Inorganic zinc and the intestinal absorption of ferrous iron.

The effect of inorganic zinc on the absorption of inorganic iron (Fe+2) from a solution was assessed in two studies on healthy male volunteers. In the first study coadministration of 344 mumol of zinc had no effect (p less than 0.5) on the absorption of 842 mumol of radiolabeled Fe, assessed by the area under plasma Fe increment time curve during the 3 (AUC3) and 6 (AUC6) h postadministration (Fe alone AUC3 = 176.4 +/- 39.3; AUC6 = 387 +/- 101; Fe + Zn AUC3 = 180 +/- 33.1; AUC6 = 396 +/- 73.1 mumol.h-1.L-1), total plasma content of 59Fe, and whole-body retention of 59Fe. In the second study only the plasma appearance of Fe was monitored. After administration of 421 mumol of Fe alone, the AUC3 and AUC6 were 167 +/- 21.2 and 429.4 +/- 57 mumol.h-1.L-1, respectively; these were reduced to 56.4 +/- 17 and 119 +/- 34 (p less than 0.002) by 421 mumol Zn and further reduced by 1048 mumol Zn to 33 +/- 15 and 43.4 +/- 23.8 mumol.h-1.L-1 (p less than 0.001), respectively. It is concluded that Zn can impair the intestinal absorption of Fe.

Adult↗

Effect of chronic octreotide treatment on intestinal absorption in patients with acromegaly.

The adverse gastrointestinal effects of octreotide, a synthetic analog of somatostatin, have not been fully elucidated. Low-dose octreotide frequently causes adverse gastrointestinal symptoms in normal individuals. We investigated the adverse gastrointestinal effects of high-dose octreotide, which is required for the normalization of growth hormone hypersecretion in some patients with acromegaly. Patients with acromegaly (N = 8) were treated with octreotide, 450 micrograms/day, then 1500 micrograms/day for two months at each dosage. Carbohydrate absorption was assessed using the D-xylose test, and fat absorption using fecal fat excretion and serum carotene concentrations, at baseline, at each dosage of octreotide, and after one month of washout. Ultrasonography was used to monitor for cholelithiasis. Growth hormone and insulin-like growth factor-I concentrations were significantly suppressed at both dosages. Adverse gastrointestinal symptoms were mild and transient. D-Xylose absorption remained normal at each dosage and after one month of washout. Fecal fat excretion increased from 7 +/- 2 to 12 +/- 2 g/24 hr (P < 0.05) after the higher dosage and resumed baseline levels after the washout. Mean fasting serum carotene levels remained normal, and carotene loading test (15,000 units three times a day for three days) was unreliable in identifying patients with high fecal fat. No new cholelithiasis was detected by ultrasonography. One of two patients with preexisting cholelithiasis developed biliary colic several days after the treatment period. Although steatorrhea was common, small intestinal absorptive capacity was otherwise unchanged by four months of high-dose octreotide treatment, which significantly suppressed growth hormone secretion in acromegalic patients.

Acromegaly↗