Effect of complex formation on drug absorption. XV. Structural requirements for enhancement of intestinal absorption of steroids by N,N-di-n-propylpropionamide.
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Animals↗
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Early stages of intestinal absorption of specific antibiodies in the newborn. An ultrastructural, cytochemical, and immunological study in the pig, rat, and rabbit.
In mammals, passive immunity is transferred from mother to offspring by transplacental passage or by intestinal absorption. The rabbit receives antibodies exclusively across the placenta, whereas intestinal absorption is the principal source of antibodies for the new-born pig. In the rat, passive immunity is transferred by both pathways. The role of the jejunal absorptive cells was investigated in these three species, by the use of specific immune globulins as tracers of protein absorption. Rabbit anti-peroxidase and anti-ferritin antibodies were injected into the jejunum of newborn pigs, rats, and rabbits, and absorption was studied over the first 2 hr. The specific antibodies were detected in glutaraldehyde-fixed tissues after in vitro treatment with the antigens, and in sera by immunological methods. Intact antibodies are transferred into the circulation of the pig and the rat, but not into that of the rabbit. In the three species, the jejunal absorptive cells take up antibodies by endocytosis. In the pig, the antibodies are transported across the epithelium in vacuoles. In the rabbit, the endocytosis of antibodies triggers a lysosomal response and all absorbed antibodies are trapped in lysosomes. In the rat, both situations are found; there is no evidence of transfer of antibody fragments into the circulation.
Animals↗
Effect of verapamil on intestinal absorption of calcium in the rat.
The effect of verapamil in vitro, and the in vivo effect of both oral and parenteral verapamil administration on intestinal absorption was tested using everted gut sacs of duodenum, jejunum, distal ileum and proximal colon in rats. In the in vivo study, the effect of verapamil on blood levels of calcium, phosphorus and 1.25(OH)2D3, was investigated and a complete calcium balance was performed. In vitro, verapamil (1.5 mM) inhibited calcium absorption by the duodenum and colon only. Oral verapamil led to a reduction in the blood level of 1.25(OH)2D3. However, both oral and parenteral verapamil had no effect on the intestinal absorption, urinary secretion and consequently on the calcium balance.
Animals↗
Effect of phosphate on the intestinal absorption of lead (203Pb) in chicks.
The effect of phosphate on the intestinal absorption of lead (203Pb2+) was examined in chicks. Absorption was determined by the in situ ligated duodenal loop technique. In one approach, diets differing in phosphate content were fed to 2-week-old chicks for a period of 7 days. With respect to the control group (1.06% P), a severe phosphate deficiency (0.16% P) decreased growth, CaBP synthesis and 203Pb absorption; a moderate phosphate deficiency (0.33% P) resulted in an increase in CaBP production and 203Pb absorption; and the high phosphate diet (2.12%) gave mean values for CaBP synthesis and 203Pb absorption intermediate between those from the chicks fed the 0.33 and 1.06% diets. 203Pb absorption was highly correlated with CaBP concentrations. In another approach, phosphate in varying concentrations was added directly to the dosing solution. In one study, phosphate addition (0.1 mM) depressed 203Pb absorption in rachitic and cholecalciferol-treated chicks. When the data were expressed in terms of absorption of the soluble 203Pb present in the intestinal lumen at the end of the absorption period, an effect of phosphate in addition to the precipitation of the insoluble lead salt was uncovered. In an experiment with normal chicks, it was observed that phosphate in the dosing solution at concentrations of 1 and 2 mM partially and significantly reversed the inhibitory effect of lower concentrations of phosphate (0.01 mM and 0.1 mM). These data demonstrate the complexity of the phosphate-lead interaction, in addition to directly showing an effect of dietary phosphate on intestinal lead absorption.
Animals↗
Intestinal absorption of beta-alanine, anserine and carnosine in rats.
Absorption beta-alanine, anserine or carnosine from rat intestine was studied in vivo by a force feeding method and in vitro using an everted sac method. Possibility of anserine and carnosine hydrolysis prior to intestinal absorption was also investigated using a glycylleucine dipeptidase-containing fraction prepared from rat intestine. The following results were obtained. 1) Anserine and carnosine were absorbed as they were from rat small intestine. 2) Both anserine and carnosine were partially hydrolyzed in vitro by the glycylleucine dipeptidase-containing fraction. Carnosine was hydrolyzed faster than anserine. The above rather conflicting results suggest that physiological amounts of anserine and carnosine might be absorbed from rat small intestine in dipeptide forms.
Alanine↗
Intestinal transport and metabolism of analgesic dipeptide, kyotorphin: rate-limiting factor in intestinal absorption of peptide as drug.
Intestinal transport and metabolism of kyotorphin (KTP) were studied in rat everted small intestine. KTP on the mucosal side was metabolized completely within 60 min, and any amounts of KTP were not detected on the serosal side. On the other hand, [D-Arg2]-KTP (D-KTP) was stable on the mucosal side to appear on the serosal side. However, N-t-butoxycarbonyl-KTP (Boc-KTP), which was metabolized on the mucosal side faster than KTP, appeared on the serosal side. In intestinal homogenate, KTP was metabolized, and the metabolic clearance (CL(met)) was decreased by peptidase inhibitors, bestatin, o-phenanthrolin and tryptophan hydroxamate. In the presence of these peptidase inhibitors, the absorption clearance (CL(abs)) of KTP was increased. The less the CL(met) of KTP was, the more the CL(abs) of KTP was. Meanwhile, Boc-KTP in intestinal homogenate was stable even in the absence of peptidase inhibitors. The CL(abs) of Boc-KTP was constant irrespective of the stability on the mucosal side. Kinetic analysis by the metabolic inhibition model indicated that the stabilization of KTP in the intestinal tissue could increase the CL(abs) up to 0.247 microl/min per cm, which was as much as the CL(abs) of stable D-KTP. These results led to the conclusion that rate-limiting process in intestinal absorption of KTP is metabolic degradation in intestinal tissue during the absorption.
Analgesics↗
Some technical precisions to a method for in vivo intestinal absorption studies.
Some modifications to the method of PONZ et al. for in vivo intestinal absorption studies using an in situ perfused segment of small intestine, under anesthesia, are described. They improve its accuracy and applicability, especially when slowly absorbed substrates are used or when volume flux measurements are desired. Calculations for the absorbed substrate and net fluid volume change determinations are reported. Several aspects of the use of the method under a single pass or a recirculation perfusion system are discussed.
Animals↗
Effects of normal alcohols on intestinal absorption of salicylic acid, sulfapyridine, and prednisolone in rats.
The rates of intestinal absorption of salicyclic acid, sulfapyridine, and prednisolone from solutions containing no alcohol or 0.5% ethanol, n-butanol, or n-hexanol were determined. At the concentrations used, ethanol did not significantly affect drug absorption. Butanol reduced the rate of absorption of sulfapyridine but did not significantly affect the absorption rates of prednisolone or salicylic acid. Hexanol reduced the rates of absorption of sulfapyridine and salicylic acid and increased the rate of absorption of prednisolone. The absorption-altering effects of the alcohols were concentration dependent and rapidly reversible. Histological studies indicated that the structure of the epithelium was not altered by the alcohols. While the absorption rate of water from the drug solutions was increased by the alcohols, their absorption-altering effects could not be attributed solely to increased water flux. In addition, the absorption-altering effects of the alcohols could not be attributed to formation of drug-alcohol complexes nor to alcohol-induced alterations in the extent of binding of the drugs to nondialyzable materials in the intestinal drug solution.
Alcohols↗
Intestinal absorption of calcium in vivo is dependent on endogenous nitric oxide.
This study examines the role of nitric oxide (NO) in the regulation of calcium absorption in the small intestine. Calcium absorption was quantified by measuring 45Ca++ transport from lumen to blood in an intestinal segment (duodenum and 20 cm of the proximal jejunum) perfused by both intraluminal and vascular routes in anesthetized rats. When administered i.v. as bolus injections, NG-nitro-L-arginine methyl ester (L-NAME, 10 mg.kg-1), an inhibitor of NO biosynthesis, decreased calcium absorption with a concomitant increase in blood pressure and a decrease in mesenteric blood flow. Conversely, the nitrovasodilators 3-morpholinosydnonimine (2 mg.kg-1) and S-nitroso-N-acetylpenicillamine (10 micrograms.kg-1), which generate NO spontaneously, both increased calcium absorption with no change in mesenteric blood flow. When infused i.v., L-NAME (3 mg.hr-1.kg-1 for 40 min) induced a decrease in calcium absorption that was reversed by the NO donor sodium nitroprusside (1.5 mg.hr-1.kg-1 when infused for the last 20 min of the 40-min L-NAME infusion). Sodium nitroprusside infusion (1.5 mg.hr-1.kg-1) caused an increase in calcium absorption that was not reversed by L-NAME (3 and 30 mg.hr-1.kg-1). The present findings suggest that NO is involved in basal calcium absorption in rat small intestine in vivo.
Animals↗
Interaction between sugars and amino acids in intestinal absorption by rat, in vivo.
The inhibitory action of L-leucine on the intestinal absorption of D-glucose and D-galactose, as well as the inhibitory action of D-galactose on the absorption of L-leucine at various concentrations by rat small intestine has been studied. The further effect was more clearly evidenced when the medium was perfunded through the intestine in a closed circuit system using a peristaltic pump.
Animals↗
Intestinal absorption of colostral lymphoid cells in newborn piglets.
Intestinal absorption of colostral lymphoid cells was studied in 23 piglets of four sows (sows A, B, C and D). From the colostrum and blood of the sows the lymphoid cells were isolated with Ficoll-Paque and labelled with technetium (Na99mTcO4). In the 7th hour after birth, 5-ml volumes of the cell suspensions were injected, following laparotomy, directly into the stomach (piglets of sow A) or into the jejunum (piglets of sow B), whereas piglets of sows C and D received the suspensions through a naso-oesophageal tube. Cryostat sections of duodenum, jejunum and lymph node samples of piglets killed by bleeding 8 h after the treatment were examined by autoradiography. It was found that lymphoid cells present in the colostrum of a piglet's own mother were absorbed from the digestive tract and, via the lymphatic vessels, were transported to the mesenteric lymph nodes. Electron microscopy revealed that absorption took place intercellularly. Colostral cells of sows other than a piglet's own mother were observed only in the epithelial layer of the mucous membrane. The lymphoid cells isolated from the sows' blood and heat-treated colostral lymphoid cells were not absorbed. The results indicate that in the pig, an animal having an epitheliochorial placenta, the colostral lymphoid cells are absorbed from the digestive tract and, hence, they can confer an active cellular immunity on the newborn piglets.
Animals↗
Intestinal absorption of glandular kallikrein in the rat.
We studied the possibility of intestinal absorption of glandular kallikrein in unanesthetized rats after administration of 5 mg of active or phenylmethylsulfonyl fluoride-inactivated pig pancreatic kallikrein (PPK). Immunoreactive PPK was measured in plasma and urine by radioimmunoassay using an antiserum to PPK that does not cross-react with rat glandular kallikrein. In addition, we studied the effect of intestinally administered active PPK on the intestinal blood flow distribution. Although immunoreactive PPK could not be detected (less than 10 ng/ml) in plasma after active PPK was administered, very small amounts were found in urine (20-40 ng/3 h). In the urine most of the PPK was in active form because over 75% could be bound to aprotinin-Sepharose. After inactive PPK was administered, immunoreactive PPK was detectable in the plasma of all rats, and urinary excretion was higher than after administration of active PPK. Blood flow distribution to the small intestine as a percentage of cardiac output was significantly greater 30 min after intestinal application of active PPK (5 mg) than after administration of the vehicle alone (1 ml of 0.9% saline). These results suggest that active and inactive PPK is absorbed from the gut in very small amounts. The finding of higher amounts of immunoreactive PPK in plasma and urine after inactive PPK was administered is probably due to the fact that the inactive form of the enzyme is not bound by the plasma inhibitors. These small amounts of kallikrein absorbed appear to have some effect on intestinal blood flow distribution.
Animals↗
Intestinal absorption of octanoic, decanoic, and linoleic acids: effect of triglyceride structure.
The influence of triglyceride structure on the intestinal absorption of specific triglycerides was investigated. A bolus of either a structured or a randomized oil was given to lymph-cannulated rats. The structured oil contained medium-chain fatty acids (MCFA) in the sn-1 and sn-3 position of the triglyceride, and linoleic acid (C18:2 n-6) in the sn-2 position, whereas in the randomized oil the same fatty acids were distributed randomly between the three positions. The absorption of MCFA was highest from the randomized oil, where approximately 33% of the MCFA were located in the sn-2 position. The absorption of C18:2 n-6 was highest from the structured oil, where C18:2 n-6 is located in the sn-2 position, indicating that the intestinal absorption is influenced by triglyceride structure, and that the absorption is enhanced for fatty acids located in the sn-2 position. Prior to lymph collection, the rats were fed either a fish oil or a vegetable oil diet. The absorption of C18:2 n-6 was highest in the rats previously fed the fish oil diet. The incorporation of the highly unsaturated fatty acids from the fish oil into the membrane phospholipids may thus influence the absorption of fat.
Animals↗
[Function diagnosis of small intestine absorption using the modified D-xylose absorption test].
Based on a biophysical model of the absorptive system a modified D-xylose test has been inaugurated, which is well suited to comprehensively assess the process of intestinal absorption. According to the author's experience of many years the test is a well-suited method for detecting changes in intestinal absorption. It excels by its high validity and reliability. Its practical accomplishment is easy and needs no expensive equipment. The method and the processing and evaluation of the measured values are described in detail.
Adolescent↗
Intestinal absorption of cytidine diphosphate choline and its changes in the digestive tract.
Intestinal absorption of cytidine diphosphate choline (CDP-choline), its structural changes in the digestive tract, and hepatic uptake have been investigated in rats using 14C-labeled (14CH3 attached to N of choline) and 3H-labeled (at C5 of pyrimidine) compounds. The results indicate that: 1)CDP-choline is relatively stable in the stomach, but is quickly degraded into cytidine and choline in the intestine; 2) The hepatic uptakes of 14C and 3H reach the maximum in two to three hours after oral administration; 3) Whereas the amount of 14C remaining in the gut is inversely related to the hepatic uptake, no similar correlation is seen with 3H-labeled CDP-choline, and 4) Extrahepatic uptake of 14C and 3H is very small. The possibility of phosphorylation in the mucosa of choline and cytidine has been discussed, based on the differences in individual broken-down products in the intestinal lumen and mucosa.
Animals↗
Physical model approach to gastrointestinal absorption of prostaglandins II: In situ rat intestinal absorption of dinoprost.
In situ absorption studies with dinoprost in the rat jejunum were carried out using a modified Doluisio technique. The absorption rate was first order. There was a sigmoidal decrease in the rate with increasing buffer pH (from 3.5 to 9.5), which strongly indicated the partitioning of weak acid species into the lipoidal membrane. An asymptotic minimum rate was attained from buffer pH 7.5 to 9.5, operationally indicative of transport of anions across aqueous pores. The importance of the aqueous diffusion layer on the mucosal side of the membrane was evident; rates at pH 3.5 and 4.5 were faster at high agitation hydrodynamics in the lumen solution. Preliminary studies showed that there was no metabolism in the lumenal solution and that metabolism occurred within the membrane. The transport mechanism involved simultaneous passive diffusion and bioconversion in the membrane because (a) a 1.5 X 10(4)-fold range in dinoprost concentration (0.014-210 microM) showed no saturable carrier-mediated tendency on the rate, (b) iodoacetic acid and indomethacin did not inhibit the absorption rate, and (c) the shape of the absorption-pH profiles was suggestive of passive diffusion. The prostaglandin did not have apparent adverse membrane and vascular effects under the conditions employed. The quantification and factorization of the physically meaningful transport parameters were accomplished using the physical model previously described. The permeability coefficients of the aqueous diffusion layer for the oscillation and static hydrodynamic situations were 0.8 X 10(-4) and 1.7 X 10(-4) cm/s, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Effects of perfusion flow rates on the intestinal absorption of carbohydrates].
The effects of five perfusion flow rates (4,5, 9, 12, 30 and 60 ml/h) on the intestinal absorption of glucose, fructose and sucrose were studied in the rat with a "temporary" Thiry-Vella loop (jejunum = 20 cm). Sucrose hydrolysis and intestinal transport of actively and passively absorbed solutes were markedly affected when the flow rates rose to a value higher than the limiting rate of 12 ml/h. With a flow rate up to 60 ml/h, glucose and fructose were absorbed at the same rate, but this was not due to thinning of the unstirred water layer. Sucrose hydrolysis was likewise completely inhibited. This result cannot be attributed to a product inhibition because of the absence of hexoses in the exit perfusate. These observations had important implications in the comparison of the intestinal absorption of many nutrients to evaluate the optimal perfusion rate corresponding to intestinal function integrity.
Animals↗
Morphine-neural interactions on canine intestinal absorption and blood flow.
Intestinal Na and H2O fluxes and blood flow were determined in extrinsically denervated or innervated ileum of fed dogs during intra-arterial (0.2, 2, 20 micrograms min-1) or intraluminal (4, 40, 400 micrograms ml-1) morphine sulphate infusion. 3H2O and 22Na were used to determine unidirectional fluxes and 3H2O clearances were used to determine total segmental and absorptive site blood flow. Net Na and H2O absorption decreased with time in innervated gut segments but were unchanged in denervated segments. Intra-arterial morphine prevented the decrease in net Na and H2O absorption in innervated segments due to increases in unidirectional absorptive fluxes. Intra-arterial morphine did not affect absorption in denervated segments. Intraluminal morphine increased net Na and H2O absorption from both innervated and denervated ileal segments due to increases in the unidirectional absorptive fluxes. Absorptive site blood flow was linearly related to unidirectional absorptive Na fluxes in each group although not with the same slopes. The increment in absorptive site blood flow vs. absorptive Na flux was greatest with luminal morphine, intermediate with intra-arterial morphine and in denervated segments without morphine and least in innervated segments. It was concluded that intra-arterial morphine inhibits an antiabsorptive effect of extrinsic nerves and that intraluminal morphine promotes an absorptive effect which could be direct or mediated through intrinsic nerves.
Animals↗