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Relationship between balance and dual tracer isotopic measurements of calcium absorption and excretion.

Calcium (Ca) absorption was measured by the balance method and the dual tracer isotopic method in 462 studies of adult women. Results for both fractional absorption and net Ca balance were similar using the 2 methods. Slightly higher values (mean difference, 0.031 +/- 0.092) were found for fractional absorption measured by the balance method than by the isotopic method. No differences in fractional absorption between the methods were seen at a fractional absorption less than 25%. Variability in the data was greater from the balance than the isotopic method. Endogenous fecal Ca excretion was directly related to Ca intake, with an estimated value of 70-80 mg/day for a Ca intake less than 200 mg/day. These findings support the usefulness and accuracy of isotope-based measures of mineral absorption. No evidence is found from these or previous data to suggest that the process of isotopic equilibration falsely increases estimates of absorption or endogenous excretion in tracer studies. Isotopic techniques allow studies of calcium absorption in diverse populations and evaluation of unique aspects of mineral metabolism not accessible through other techniques.

Absorption↗

Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype.

The finding that the link between polymorphism at the vitamin D receptor (VDR) gene and rates of bone loss from the femoral neck in postmenopausal women is enhanced at low calcium intakes suggests that intestinal calcium absorption is a site of differential action of the VDR alleles. 1,25-Dihydroxyvitamin D [1,25-(OH)2D] and its receptor mediate active calcium transport, the major mechanism of calcium absorption at low calcium intakes. We compared fractional calcium absorption in healthy late postmenopausal women with (bb) and without (BB) the BSM-1 restriction site. In 60 women (26 BB and 34 bb), we measured calcium absorption and plasma 1,25-(OH)2D after 2 weeks on a high (1500 mg/day) and 2 weeks on a low (< 300 mg/day) calcium intake. The mean 45Ca absorption indexes were similar in the two groups on the high calcium intake [19.01 +/- 1.12% (+/- SEM)/L in BB and 20.45 +/- 0.97%/L in bb; P = 0.346] and differed significantly on the low calcium intake (20.57 +/- 1.10%/L vs. 23.66 +/- 0.95%/L; P = 0.044). Calcium restriction induced similar percent increases in plasma 1,25-(OH)2D, but the BB group had a smaller increase in the fractional 45Ca absorption index [7.8 +/- 3.8% (+/- SEM) vs. 20.7 +/- 3.3% in bb; P = 0.016; increments adjusted for initial absorption value]. In conclusion, compared to women with the bb variants, women with BB allelic variants of the VDR have reduced calcium absorption efficiency on low calcium intake, consistent with a functional defect in the intestinal VDR. The impact of this heritable difference is reduced at higher calcium intakes.

Absorption↗

Activation of P2Y receptor enhances high-molecular compound absorption from rat ileum.

While there are no reports concerning the effects of extracellular nucleotides on the intestinal absorption of drugs, it is well known that extracellular nucleotides are important regulators of intestinal epithelial ion transport. This report using fluorescein isothiocyanate dextran 4000 (FD-4) as the model compound is the first to investigate the effects of purine nucleotides on absorption of poorly absorbed drugs from intestine. ATP enhanced the absorption of FD-4 from rat ileum in a concentration-dependent manner. ADP also enhanced the absorption of FD-4. Other purine nucleotides (adenosine, AMP, UTP and UDP) did not show an absorption-enhancing effect. The absorption-enhancing effect by ATP was inhibited by suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS), which are known P2 receptor antagonists. Additionally, 2-methylthio ATP (a P2Y receptor agonist) enhanced the absorption of FD-4, but alpha,beta-methylene ATP (a P2X receptor agonist) did not. These findings suggest that activation of the P2Y receptor may improve the absorption of water-soluble and high-molecular compounds from the ileum.

Adenosine Triphosphate↗

Gastrointestinal transit and drug absorption.

The gastrointestinal (GI) absorption of orally administered drugs is determined by not only the permeability of GI mucosa but also the transit rate in the GI tract. It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. The reason why the residence time is also a critical factor for drug absorption is that there is the site difference in absorbability for some drugs. We have developed the GI-Transit-Absorption Model (GITA Model) to analyze and predict the drug absorption kinetics by taking into account both the two factors, ie. GI transit and drug absorbability including its site difference. GITA Model has been already evidenced to be very useful for estimating the absorption kinetics of drugs with various characteristics and applied to assess the human data in combination with the gamma scintigraphy. In this review, the importance of GI transit rate in determining the absorption kinetics and the bioavailability of orally administered drugs is discussed mainly employing GITA Model and the results obtained by the model.

Administration, Oral↗

Influence of liver disease on phenolsulfonphthalein absorption from liver surface to examine possibility of direct liver surface application for drug targeting.

We have examined the influence of liver disease on drug absorption from the liver surface membrane, regarded as the first barrier for drug targeting to the liver. The main purpose of this study is to examine the possibility of direct liver surface application as a drug targeting method. We employed rats intoxicated with carbon tetrachloride (CCl(4)) or D-galactosamine (GAL) as the liver disease model, and examined drug absorption characteristics after application to the liver surface, by utilizing a cylindrical diffusion cell. In the liver-intoxicated rats, about 90% of a low molecular weight drug, phenolsulfonphthalein (PSP), as a model was absorbed from the liver surface in 6 h, similar to the normal rats (no treatment). Although the absorption rate was increased in the CCl(4) group, whereas slightly retarded absorption was observed in GAL group, there should be no serious problem for the clinical use of liver surface application. The PSP absorption from the liver surface in the CCl(4) group was indicated to obey first-order kinetics by elimination profile from the diffusion cell. The first-order absorption rate constant K(a) values of PSP from the liver surface, obtained by a compartment model and elimination profile, were increased 1.3-fold in the CCl(4) group compared to the control. Moreover, we performed drug application to the liver surface in the peritoneal cavity to assume clinical use. The K(a) of PSP in the CCl(4) group was about 4-fold larger than in the normal group, implying the importance of estimating changes in peritoneal drug absorption as a result of liver disease. Consequently, it is expected that there will be no marked decline in the absorption rate from the liver surface in a liver disease state, leading us to apply this administration method for liver targeting.

Absorption↗

Effects of mitomycin C, 5-fluorouracil and cyclophosphamide on drug absorption, enzyme activities and mucosal lipid composition of intestine.

The effect of a single intravenous or oral administration of mitomycin C (MMC), 5-fluorouracil (5-FU) or cyclophosphamide (CP) on drug absorption was studied in rats in relation to changes in membrane characteristics. At 48 h after pretreatment, a differential effect on the absorption of sulfanilamide and L-tryptophan was observed in in situ recirculation experiments. Intravenous MMC administration suppressed the absorption of both sulfanilamide and L-tryptophan to a similar extent as a higher oral dose of this agent. Dosing with 5-FU via both routes caused the largest but almost equal suppression of L-tryptophan absorption. However, CP had no effect on the absorption of the two drugs. Differences in these effects were considered to reflect their pharmacological and pharmacokinetic properties. Absorption of drugs from the small intestine had a positive correlation with small intestinal wet weight regardless of the antitumor drug used, pretreatment doses and routes of administration and the results indicated that the change in absorptive surface area played a major role in this phenomenon. Toxicity to intestinal mucosa was shown to derive from an effect on dividing cells in the crypts because MMC and 5-FU preferentially decreased thymidine kinase activity. However, at the membrane level, increased mucosal membrane permeability was also confirmed by measuring the release rates of D-glucose from liposomes consisting of mucosal total lipids obtained from the antitumor drug-treated rats. Pretreatment with lipophilic and polymeric prodrugs of MMC did not exhibit any effect on drug absorption and thus, the possibility of alleviation of toxicity and adverse reactions via the prodrug approach was suggested.

Animals↗

Effect of carrier-mediated transport system on intestinal fosfomycin absorption in situ and in vivo.

Intestinal absorption mechanism of fosfomycin (FOM), a water-soluble and small molecular antibiotic, at the clinical dose level was examined by both in situ single-pass perfusion technique of rat small intestine and oral administration in rat in vivo. Analyzing the luminal concentration-dependence of FOM absorption rates in situ by the equation composed of two terms of carrier transport of Michaelis-Menten type and simple-diffusion, apparent Michaelis constant (Kt), maximal transport velocity (Jmax), and first-order diffusive absorption clearance (Kd) were 1.13 mM, 2.54 nmol/min/cm length, and 0.551 microliters/min/cm length, respectively. At the low FOM concentration in the lumen (0.1 mM), its absorption was reduced to about 60% of the control by inorganic phosphate ion at 1.0 mM in the same manner as the uptake in brush border membrane vesicles of rat small intestine (BBMVs) in vitro. Both the glycol form of FOM at 10 mM, the hydrolyzed metabolite of FOM in the stomach juice, and FOM itself at 10 mM reduced FOM absorption by about 50%, indicating the metabolite to be transported by the same carriers as those of FOM. At the higher FOM concentration (5 mM), its absorption was not reduced by any inhibitor described above. No inhibitory effect of 50 mM phosphate ion on FOM absorption following the oral dosing of 20 mg/kg FOM was found. It was concluded that FOM absorption at the clinical dose (10-20 mg/kg) is barely inhibited by the carrier-mediated system via phosphate transport system observed in the in vitro BBMVs.

Animals↗

Effect of taurine on drug absorption from the rat gastrointestinal tract.

Effect of taurine on drug absorption from the rat gastrointestinal tract was investigated by using in situ loop method for the stomach and in situ recirculation method for the small or large intestine. Aspirin absorption from the stomach or the small intestine was enhanced by the presence of taurine, but not from the large intestine. The absorption enhancement effect of taurine was not only site-specific, but also substrate-specific. Taurine increased the absorption of aminopyrine from the small intestine, but not from the stomach. On the other hand, the absorption of salicylamide, o-methoxybenzoic acid and o-ethoxybenzoic acid was enhanced in the stomach, although they were not influenced in the small intestine. Furthermore, among the taurine analogues investigated only homotaurine showed the taurine-like action in the small intestine. Glycine also increased the gastric absorption of aspirin. These effects were observed neither by the pretreatment of the intestine with taurine, nor by i.v. administered taurine. Taurine at the site of drug absorption, even at a low concentration, seems to influence the drug absorption due to its effect on the permeability characteristics of the mucosal membrane.

Animals↗

Studies on sustained-release suppositories. I. Effect of alginic acid addition on rectal absorption of bacampicillin in rabbits.

Sustained-release suppositories of bacampicillin (BAPC) were prepared by the use of the adduct which was precipitated from an aqueous solution containing BAPC and alginic acid (Alg). As the suppository base, Witepsol H-15 and macrogol were used. Absorptions of BAPC from the suppositories were prolonged in rabbits, but the bioavailabilities were decreased compared to that after administration of BAPC alone. However, these absorptions were improved enormously by the addition of surface-active agents, that is, an excellent prolonged absorption and high bioavailability were obtained. Interestingly, similar prolonged absorption could be obtained only by mixing Alg with BAPC in a suppository base. Further, this absorption rate was found to be controlled by the amount of Alg addition. The absorption profiles from a suppository containing the mixture differed from that containing the adduct in exhibiting both high plasma level and prolonged absorption. This may be due to simultaneous fast absorption of BAPC itself and formation of the adducts. Thus, it seemed that BAPC preparations containing Alg may be practically useful as a rectal preparation with prolonged action and giving a high plasma level.

Alginates↗

[Transdermal delivery of drugs and enhancement of percutaneous absorption].

This paper describes 1) the drug delivery through the skin to produce systemic effects, 2) the enhancement of percutaneous absorption by absorption enhancers, heating and complex formation, 3) the mechanism for the enhancement effect by enhancers, 4) the percutaneous absorption of peptides, and 5) the pharmacokinetic analysis for percutaneous absorption. 1,3-Dinitroglycerin, indomethacin (IND) and many drugs were efficiently absorbed via rat and rabbit skins in the presence of some enhancers, and using a microporous membrane therapeutic plasma concentrations were maintained for a long time. Enhancement of percutaneous absorption by the complex formation with fatty acid was observed for propranolol (PL) in vitro and in vivo. Heating at 42-45 degrees C also enhanced the percutaneous absorption dramatically, with decreased activation energies. The following mechanisms for the enhancement effect by enhancers were found: a) an increase in the fluidity of the stratum corneum lipids and reduction in the diffusional resistance to permeants, b) the removal of intercellular lipids and dilation between adherent cornified cells, c) an increase in the thermodynamic activity of drugs in vehicles, d) the exfoliation of stratum corneum cell membranes, the dissociation of adherent cornified cells and elimination of the barrier function. Peptides such as enkephalin, elcatonin and insulin were effectively absorbed through the skin in the presence of some enhancers and specific inhibitors, with no proteolytic degradation. The pharmacokinetic model with two parallel absorption processes, lipidic and aqueous pore transport pathways, in skin could adequately describe the percutaneous absorption of IND, PL and valproic acid. With peptides, a kinetic model including zero-order input rate, first-order permeation rate and first-order degradation rate was able to describe well the steady-state flux of peptides.

Animals↗

Inhibitory effects of psyllium on rat mineral absorption were abolished by reduction of viscosity with partial hydrolysis.

Psyllium husk, a highly viscous fiber, has beneficial effects for health, but has been reported to inhibit absorption of calcium. The present study found the effects of fiber viscosity on calcium, magnesium, and zinc absorption with partially degraded psyllium preparations to be one fifth viscosity (LD-HP) and one seventieth viscosity (HD-HP) using normal and ovariectomized rats. Magnesium absorption was reduced with ingestion of intact psyllium (50 g/kg diet) for 4 weeks but this reduced absorption was increased with lower viscous psyllium preparations. Moreover, the absorption in the HD-HP group was higher than in the control group (100 g cellulose/kg diet) in ovariectomized rats. Changes in calcium and zinc absorption were similar to those in magnesium absorption. Cecal pH was reduced only in rats fed HD-HP in both normal and ovariectomized rats. These results indicate that reduction of psyllium viscosity tends to counter inhibitory effects on mineral absorption.

Animals↗

Effects of osmolality on water, electrolytes and VFAs absorption from the isolated ruminoreticulum in the cow.

Effect of the osmolality on the absorption of water, electrolyte and VFAs from the isolated ruminoreticulum under normal feeding condition were investigated in a series of the study to evaluate the rumen as a potential site of absorption in oral fluid therapy of adult cattle. Thirty of 40 l of the test solutions with varying osmotic pressure (100, 200, 300 and 500 mosmol/L, pH 6.8) were prepared using different concentrations of electrolytes and VFAs. These were infused into the isolated and emptied ruminoreticulum, and the absorption rate of water and each components were studied for 3 hrs. Marked absorption of water was observed with solutions more hypotonic than rumen fluid, the extent of which was more extensive with less osmotic pressure; the absorption rate as high as 47.6% was obtained with a solution 100 mosmol in osmotic pressure. When hypertonic solution (500 mosmol/L) was infused, however, water was transported on the contrary from the blood to the rumen. Absorption rates of electrolytes such as Na, K and Cl were increased according to the elevation of osmolalities and their concentrations in the test solutions. VFAs were also absorbed in large quantities (23.9-74.5%) in any test solutions, though the absorption rates were significantly decreased with the elevation of osmolalities. These results may indicate that the ruminal wall has a high absorptive function for water, electrolytes and VFAs when the osmolalities and the concentration of solutes in the ruminal fluid are maintained within a certain range. Furthermore, it is thought that they may work as a rational support for a possible oral fluid therapy even in adult cows.

Acetates↗

Lanthanides enhance pulmonary absorption of insulin.

In an effort to investigate the enhancement effect of lanthanide ions (Ln3+) on the absorption of larger molecules from the pulmonary pathway, insulin (mol. wt. = 5730) was chosen as a model peptide. The absorption of insulin preadministered or coadministered with Ln3+ from the lung was investigated by means of an in situ pulmonary absorption experiment. The enhancement absorption of insulin by Ln3+ ions was evaluated by calculating the various bioavailabilities (Fr) of insulin from pulmonary absorption. Moreover, the temporal change of Gd content in serum was also investigated. Results showed that the promoting effect of Ln3+ on the bioavailability of insulin is closely related to its species, concentration, and delivery order. The effect of the median Ln3+ series was remarkably greater than that of light and heavy Ln3+. The anionic form of Gadolinium (Fr = 68.4%) seemed to be more effective compared with its cationic form (Fr = 59.5%). Coadministration of Gd3+ with insulin (Fr = 80.1%) was the most effective in increasing insulin absorption from the lung. Gd3+ was rapidly absorbed and metabolized to a normal level after 4 h. It was suggested that lanthanides in a very low concentration might become potent absorption enhancers to improve absorption of larger molecules via the pulmonary pathway.

Absorption↗

Relationship between absorption of radiolabeled soluble insulin, subcutaneous blood flow, and anthropometry.

OBJECTIVE: To evaluate the interrelationships between the rate of absorption of soluble insulin, SCBF, and anthropometry in normal subjects. RESEARCH DESIGN AND METHODS: In 12 normal men (age range 23-30 yr, BMI 18.2-41.3 kg/m2), simultaneous assessment of the absorption of 125I-labeled soluble insulin and SCBF (99mTc clearance) was performed, on separate study days, for the anterior abdominal wall, anterior midthigh, and the upper arm sites. Each site was examined in a randomized order on two separate occasions. Absorption of 125I-soluble insulin was determined by external monitoring of residual radioactivity levels at the injection site for 6 h postinjection. Residual radioactivity level-time curves, including the characteristic early phase of slow absorption of soluble insulin (the lag phase), were described using two- and three-parameter biexponential models. Anthropometric measurements included BMI, ultrasonic measurement of the subcutaneous adipose tissue layer, and caliper skin fold thickness at the anterior abdominal wall, biceps, triceps, anterior midthigh, and subscapular sites. RESULTS: A highly significant positive relationship was observed between the rate of absorption of 125I-soluble insulin and SCBF (rS = 0.44-0.52; P < 0.01-0.001). The duration of the lag phase was inversely correlated with SCBF (rS = 0.34 - 0.51; P < 0.01-0.001). Inverse relationships also were observed for the subjects' degree of adiposity with the rate of soluble insulin absorption (rS = -0.43(-)-0.71; P < 0.001) and SCBF (rS = -0.27(-)-0.62; P < 0.05-0.001). Significantly shorter lag phase was observed for the abdominal site compared with thigh and arm injection sites (P < 0.05-0.01). CONCLUSIONS: The rate of absorption of soluble insulin, including during the lag phase, is positively correlated with SCBF. Increasing adiposity prolongs the duration of the early lag phase and reduces the rate of absorption of soluble insulin and SCBF.

Absorption↗

Site of mineral absorption in lactating cows fed high-fat diets.

Five lactating Holstein cows with ruminal and duodenal cannulas were used in a 5 x 5 Latin square to determine the site of mineral absorption and effects of sources and amount of dietary fat on apparent absorption. Cows were fed (DM, 17.4 +/- .8 kg/d) chopped alfalfa hay, alfalfa haylage, corn silage, and concentrate at 1:1:1:2 (DM) at 12-h intervals. Calcium salts of palm fatty acid distillate (CS) or animal-vegetable (AV) fat were 0% (control), 2.5% (low, L), or 5.0% (high, H) of the diet DM. After 2 wk of adaptation, duodenal and fecal grab samples were collected at 7-h intervals for 5 d and composited by animal. Calcium intake increased (P < .05) with high-fat diets (195 vs 170 g/d), whereas Mg intake remained unchanged (54.3 +/- 9.0 g/d). Apparent absorption, estimated by Cr2O3, was regressed on Ca or Mg intake (grams/day) and fatty acid (FA) intake (grams/day). Total absorption of Ca (grams/day) = -37.4 + .264 Ca (P = .07, R2 = .14). Ruminal absorption of Mg was independent of FA intake, and magnesium was secreted posterior to the duodenum. Total tract Mg absorption (grams/day) was described by -7.685 + .464 Mg -.0044 FA (P < .0005, R2 = .46). Fat intake decreased (P < .05) total tract Mg absorption, and Ca absorption was decreased by high fat compared with low fat intake (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

Effect of supplemented magnesium from magnesium oxide or dolomitic limestone upon digestion and absorption of minerals in sheep.

Three metabolism trials were conducted with six lambs fitted with abomasal and ileal cannulae to determine the site of supplemental Mg absorption when supplied as dolomitic limestone or magnesium oxide. Magnesium intake was 1.09 g/d for the lambs fed the control diet and 2.21 and 2.10 g for those fed the dolomitic limestone and magnesium oxide supplemented diets, respectively. Irrespective of its source, the major site of Mg absorption was the preintestinal region. Magnesium was secreted in the small intestine in lambs fed all three diets. Magnesium supplementation resulted in an increase (P less than .05) in preintestinal Mg absorption, with magnesium oxide having the highest value. Supplementation had no effect (P greater than .05) on secretion or absorption of Mg from the small and large intestines or total retention of Mg. With all three diets, the major site of Ca absorption was the stomach region with additional absorption taking place in the large intestine. Calcium was secreted in the small intestine of lambs fed all treatments. Generally, K, Na and P were secreted in the preintestinal region and absorbed from the small and large intestines. The major site of K and P absorption appeared to be the small intestine and for Na, the large intestine. Serum minerals were unchanged (P greater than .05) due to treatment, but the levels of Mg, K and inorganic P tended to be higher in lambs supplemented with either of the Mg sources. It appears that the greater utilization of Mg from magnesium oxide vs dolomitic limestone is due to greater absorption of Mg from the forestomach region.

Animals↗

Net absorption of glucose and nitrogenous compounds by lactating Holstein cows.

Net absorptions from portal-drained viscera of glucose, ammonia nitrogen, alpha-amino nitrogen, and urea nitrogen were measured in four Holstein cows in first lactations. Cows were fed for ad libitum consumption a completely mixed, 60:40 corn silage:supplement diet (dry basis) in two equal feedings at 12-h intervals daily. Portal blood flow (dye dilution) and net absorption (portal-arterial difference times portal blood flow) were measured at hourly intervals for 12 h for all cows 4 and 8 wk postpartum and for two cows 4, 8, 12, 16, and 20 wk postpartum. Apparent digestibilities of dry matter and nitrogen were measured immediately after net absorption. Milk yield and composition were measured with absorption and digestion. Mean daily dry matter intake and milk yield were 14.1 +/- .6 and 23.8 +/- 1.8 kg. Portal blood flow was not affected by time of day or weeks postpartum; mean was 1371 +/- 123 liters/h. Net absorption of glucose was negative, indicating no uptake of glucose from dietary sources. Means (g/day) for nitrogenous sources were: nitrogen intake 387, fecal nitrogen 121, urinary nitrogen 146, milk nitrogen 116, net ammonia nitrogen absorption 149, net alpha-amino nitrogen absorption 137, and net loss of urea nitrogen from blood to the gut 93. Net absorption of amino nitrogen and alpha-amino nitrogen in blood was greater than in plasma; corresponding losses of urea nitrogen and glucose to the gut were greater from blood than plasma.

Amines↗

True absorption of calcium and phosphorus from alfalfa and corn silage when fed to lactating cows.

A crossover experimental design with an extra period was used with four lactating cows (645 kg BW) and two diets to measure the true absorption of Ca and P from alfalfa hay and corn silage. True absorption was calculated after dosing cows intravenously with 45Ca and 32P to measure endogenous fecal losses. In alfalfa hay and alfalfa-corn silage diets, the Ca and P that came from the hay or hay and silage fraction was 94 and 98% and 63 and 84%, respectively. Cows ate more DM (22.7 vs. 20.6 kg/d) and produced more FCM (35.2 vs. 32.0 kg/d) when consuming alfalfa-corn silage compared with alfalfa hay. True absorption of Ca from alfalfa-corn silage was greater (42.2%) than from alfalfa hay (24.6%). Partial true absorption of Ca from alfalfa hay was 23.5% and from corn silage 51.5%. True P absorption for total diet was similar for both alfalfa hay (64.4%) and alfalfa-corn silage (74.6%). Partial true absorption of P from alfalfa hay (67.3%) was different from that from corn silage (80.0%). Fecal endogenous Ca excretion was nearly double the value (31 vs. 16 mg/kg BW) currently used by NRC. True absorption of Ca from alfalfa was lower and from corn silage was higher than currently used in NRC feeding standards. True absorption of P was higher than values currently used by NRC.

Animal Feed↗