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PubMedDate not supplied

Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport.

The aim of the present study is to evaluate the quantitative contribution of passive permeability to P-glycoprotein-mediated (P-gp-mediated) efflux and the functional activity of P-gp in determining intestinal absorption of drugs, and demonstrate the relationship between efflux parameters and intestinal permeability. MDRI-MDCKII cell monolayer permeability, human intestinal absorption (HIA), and solubility data were systematically collected from the literature. Drugs were classified as a total of 63 P-gp substrates (P-gpS) and 73 nonsubstrates (NS) on the basis of efflux ratio or calcein AM inhibition and ATPase activity assays. Efflux parameters, efflux ratio (ER) and absorption quotient (AQ), were correlated to the monolayer permeability. MDRI-MDCKII cell monolayer permeability characteristics were found to be distinctly different between P-gpS and NS datasets. The ER for P-gpS was found to increase with absorptive permeability until 20 nm.s(-1), but reduced for P-gpS with high absorptive permeability. The AQ showed a linear inverse relationship with absorptive permeability. Overall, efflux parameters, ER and AQ, indicated that the transport of P-gpS with moderate passive permeability is highly attenuated by P-gp, while passive permeability overrules the P-gp-mediated efflux for high-permeability molecules. Most of the P-gpS were found towards the upper limits of molecular weight (>500) and calculated total polar surface area (>75 A(2)). This dataset indicated that unfavorable chemical features of P-gpS limit passive permeability and thus are more susceptible to P-gp-mediated efflux. In conclusion, passive permeability versus P-gp-mediated efflux determines intestinal permeability of P-gpS, where P-gp limits absorption of only moderately permeable compounds. Thus, integrating these factors with drug characteristics of the Biopharmaceutics Classification System (BCS) class better predicts the functional role of P-gp in limiting intestinal drug absorption.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Surface active agents as enhancers of alveolar absorption.

PURPOSE: Small solutes which are deposited in the alveoli by aerosol inhalation will be absorbed across the alveolo-capillary barrier. Inhalation of dioctyl sodium sulfosuccinate (DOSS) enhances absorption while having little or no effect on lung function, suggesting that surface active agents may be used as enhancers of alveolar absorption of inhaled pharmaceuticals. The purpose of this study was to examine the effects of a selection of different surface active agents on alveolar absorption. METHODS: The absorption of 99mTc-diethylene triamine pentaacetate (99mTc-DTPA) from the lungs was studied in rabbits. We studied five different surface active agents: DOSS, sodium glycodioxycholate (GDCA), sodium lauryl sulphate (NaLS), lysophosphatidyl choline (LPC) and polyoxyethylene-23-laurylether (P23LE). RESULTS: DOSS and GDCA both dramatically enhanced the absorption of 99mTc-DTPA. There was a moderate effect of NaLS, no significant effect of LPC and P23LE reduced the rate of absorption. None of the compounds affected gas exchange or lung compliance. CONCLUSIONS: There is a wide spectrum of effects of inhaled surface active agents on the alveolar absorption of 99mTc-DTPA. Ionic compounds such as DOSS and GDCA have the greatest effect, and further studies of these classes of surface active agents for use as enhancers of alveolar absorption of pharmaceuticals seem warranted.

Absorption↗
PubMed1998

Investigation of absorption kinetics by the phase plane method.

PURPOSE: To develop a simple approach for investigating absorption kinetics, which does not require modeling assumption or intravenous data. METHODS: The concentration (C) -time (t) data are plotted as a phase plane plot (dCldt versus C). Errorless C,t data were generated from one and two compartment models employing first-order, zero-order and Michaelis-menten input kinetics, and the phase plane plots were constructed. A simple test based on the ratio of slopes of the separate linear regression analyses of absorption and elimination data of the phase plane plot is proposed to justify or not the presence of zero order input kinetics. Errant data were used to assess the performance of the test developed. Literature data of theophylline and nitroglycerin formulations were analyzed using the phase plane plot. Input rate-time profiles were constructed for one compartment model drugs utilizing the data of the phase plane plot. RESULTS: The geometric forms of the phase plane plots derived form the errorless data of the various pharmacokinetic models were found to be indicative of the absorption kinetics. Very good resulted were obtained when the test for he discernment of absorption kinetics was applied to errant data. Zero-order absorption kinetics were justified (i) for the transdermal absorption of nitroglycerin and (ii) only for a certain period of time, for the gastrointestinal absorption of theophylline. CONCLUSIONS: Investigation of absorption kinetics can be accomplished with the phase plane method. The cumulative character of the classical percent absorbed versus time plots can be misleading in justifying the presence of zero-order input kinetics.

Absorption↗
PubMed1998

Reduced systemic availability of an antiarrhythmic drug, bidisomide, with meal co-administration: relationship with region-dependent intestinal absorption.

PURPOSE: The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. METHODS: Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. RESULTS: Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (-13%) was substantially smaller than the reduction (from -43% to -63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 +/- 5.7% and 23.7 +/- 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased Cmax but not AUC, while viscous homogenized solid meals decreased both Cmax and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. CONCLUSIONS: The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.

Animals↗
PubMed1995

Absorption of an oxytocin antagonist (antocin) and a vasopressin analogue (dDAVP) through a standardized skin erosion in volunteers.

PURPOSE: Transdermal administration of the peptides [Mpa1, D-Tyr (Ethyl)2, Thr4, Orn8]-oxytocin (antocin) and [Mpa1, D-Arg8]-vasopressin (dDAVP) was studied in healthy volunteers. METHODS: A standardized skin erosion was formed preliminary by suctioning. The peptides were administered in plastic reservoirs through a 5 mm erosion and the absorption was followed for a six-day period with plasma concentration determinations on days 1, 3 and 6 with refilling the reservoirs daily with 15 microns and 10 mM solutions of dDAVP and antocin, respectively. Fourteen healthy non-smoking volunteers divided equally between the sexes, participated in the study. Plasma concentrations were measured using specific radioimmunoassays. Reservoir concentrations and metabolic stability of the peptides were determined using reverse-phase HPLC. RESULTS: Both antocin and dDAVP were absorbed across the skin erosion. The absorption pattern was biphasic with a high initial absorption during days 1 and 2 followed by a lower absorption on days 3 and 6. The absorption on day 1, which was estimated at more than 50% for both peptides during a 24 h period, corresponded to a simultaneous decrease in peptide concentration in the reservoirs. The extent of absorption for antocin on days 3 and 6 was 1/3 to 1/6, respectively, of that observed on day 1. Antocin was minimally degraded in the skin reservoir while dDAVP was intact. However, accumulation of cellular material appeared in the antocin reservoirs. The absorption of antocin was reduced by exposure to intact skin surrounding the skin erosion. No pain was experienced and no scar formation was observed. CONCLUSIONS: The observed biphasic absorption may be a consequence of the mild inflammatory response occurring subsequent to eroding the skin. The standardized skin erosion may provide a route for the short-term delivery of otherwise poorly absorbable peptide and protein drugs.

Absorption↗
PubMed1995

A new method for estimating dermal absorption from chemical exposure. 3. Compared with steady-state methods for prediction and data analysis.

PURPOSE: This paper compares unsteady-state and steady-state methods for estimating dermal absorption or analyzing dermal absorption data. The unsteady-state method accounts for the larger absorption rates during short exposure times as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. METHODS: Example calculations for dermal absorption from aqueous solutions are presented for five environmentally relevant chemicals with molecular weights between 50 and 410 and log10Kow between 0.91 and 6.8: chloromethane, chloroform, chlordane, 2,3,7,8-TCDD, and dibenz(a,h)anthracene. Also, the new method is used to evaluate experimental procedures and data analyses of in vivo and in vitro permeation measurements. RESULTS: In the five example cases, we show that the steady-state approach significantly underestimated the dermal absorption. Also, calculating permeability values from cumulative absorption data measured for exposure periods less than 18 times the stratum corneum lag time will overestimate the actual permeability. CONCLUSIONS: In general, steady-state predictions of dermal absorption will underestimate dermal absorption predictions which consider unsteady-state conditions. Permeability values calculated from data sets which include unsteady-state data will be incorrect. Strategies for analyzing in vitro diffusion cell experiments and confirming steady state are described.

Animals↗
PubMed1997

Urinary recovery of lactulose compared to D-xylose absorption kinetics in HIV patients with diarrhea and weight loss.

Using a kinetic model of D-xylose absorption, we have previously shown that there is severely impaired absorption of D-xylose in HIV patients with diarrhea and weight loss. The absorptive defect is characterized by an increased rate constant for nonabsorptive loss of D-xylose, Ko, and a decreased absorptive rate constant, Ka, and is unrelated to histology or the presence of pathogens. It is not known if there is also abnormal paracellular transport in these patients. We have extended our observations in these patients by including a measurement of paracellular transport, lactulose absorption. Nine HIV patients with chronic diarrhea, weight loss, and no detectable intestinal pathogens, two healthy volunteers, and three non-HIV patients with chronic diarrhea (two functional and one with scleroderma) were enrolled. Of the nine HIV patients, six had diminished bioavailability of D-xylose, F (range: 19-52%, normal >70%), and elevated rate constant for nonabsorptive loss, Ko (range: 0.54-1.35/hr, normal <0.353/min). Four of the six also had decreased Ka (range: 0.09-0.36/hr, normal >0.634/min). Only one of these six had increased lactulose recovery (3.51%, normal <0.5%). Two of three patients with normal kinetic parameters of D-xylose absorption had increased lactulose urinary recovery (1.92%, 2.61%). In conclusion, lactulose absorption is increased in some patients with HIV-related diarrhea who have normal D-xylose absorption, suggesting a paracellular mechanism for diarrhea in some patients with AIDS enteropathy.

Diarrhea↗
PubMed1994

The influence of net water absorption on the permeability of antipyrine and levodopa in the human jejunum.

Food ingestion can influence the absorption of levodopa in the intestine and thereby contribute to fluctuations of motor functions in Parkinson patients. Obstruction of the active transport of levodopa by amino acids can be one factor. Paracellular drug absorption, a route proposed to be influenced by net transport of water across the intestinal epithelium, might occur for a small and hydrophilic drug such as levodopa. In the present study we studied how luminal L-leucine (60 mmol/L), alone or combined with hypotonicity, might stimulate net water absorption, and levodopa uptake in the human small intestine, since this possibly can contribute to the variable intestinal absorption of levodopa. The Loc-I-Gut perfusion technique was used in 10 healthy volunteers to study the effects of induced net fluid absorption on the small intestinal absorption of levodopa (2.5 mmol/L). An induced net fluid absorption was observed only when L-leucine was combined with a hypoosmolar perfusion solution. However, this did not enhance the intestinal permeability of levodopa. In conclusion, we suggest that the variability in the absorption of levodopa in Parkinson's disease cannot be explained by differences in transmucosal water flux in the human small intestine.

Antipyrine↗
PubMed2004

Evaluating barriers to bioavailability in vivo: validation of a technique for separately assessing gastrointestinal absorption and hepatic extraction.

PURPOSE: The purpose of this study was to develop and validate a method for separately evaluating the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability (BA). The method was validated using five reference compounds known to have different absorption and hepatic extraction properties. Dose-dependence was also investigated for one reference compound. METHODS: Five reference compounds, amoxicillin, antipyrine, atenolol, propranolol, and testosterone, were administered as a cassette intravenouly (IV), via the hepatoportal vein (IPV), intraduodenally (ID), and intracolonically (IC) to male Sprague-Dawley rats. Blood samples were taken at nine time points, and the compounds were extracted from plasma using solid phase extraction. Plasma concentrations of each compound were determined using Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS). Pharmacokinetic parameters including bioavailability were calculated for each compound for each route of administration. RESULTS: Testosterone BA was less than 10% by ID, IC, and IPV routes, due to high hepatic extraction, consistent with its high systemic clearance (63 ml x min(-1) x kg(-1)) and short terminal plasma half-life (23 min). The IPV BA of amoxicillin was 95%+/-6% indicating the absence of hepatic extraction in the rat, but with an ID BA of approximately 39% suggesting incomplete GI absorption to be the main barrier to bioavailability. Absorption was poor from the colon, demonstrating site-dependence consistent with literature reports of site-dependent absorption. Low oral BA of propranolol was due in part to first-pass hepatic extraction (IPV BA of 36%). The IPV BA of propranolol was dose-dependent, most likely due to saturation of the P450 enzymes. Atenolol was incompletely bioavailable due to incomplete intestinal absorption, with no contribution of hepatic first-pass metabolism. Antipyrine was highly bioavailable by all routes. CONCLUSIONS: This in vivo rat model is demonstrated to be useful for identifying and quantifying the causes of incomplete bioavailabilty. It separately evaluates intestinal absorption, hepatic extraction, and site-dependent absorption. Concentration-dependence of saturable processes can also be examined.

Amoxicillin↗
PubMed2004

Enhancers of iron absorption: ascorbic acid and other organic acids.

Ascorbic acid (AA), with its reducing and chelating properties, is the most efficient enhancer of non-heme iron absorption when its stability in the food vehicle is ensured. The number of studies investigating the effect of AA on ferrous sulfate absorption far outweighs that of other iron fortificants. The promotion of iron absorption in the presence of AA is more pronounced in meals containing inhibitors of iron absorption. Meals containing low to medium levels of inhibitors require the addition of AA at a molar ratio of 2:1 (e.g., 20 mg AA: 3 mg iron). To promote absorption in the presence of high levels of inhibitors, AA needs to be added at a molar ratio in excess of 4:1, which may be impractical. The effectiveness of AA in promoting absorption from less soluble compounds, such as ferrous fumarate and elemental iron, requires further investigation. The instability of AA during food processing, storage, and cooking, and the possibility of unwanted sensory changes limits the number of suitable food vehicles for AA, whether used as vitamin fortificant or as an iron enhancer. Suitable vehicles include dry-blended foods, such as complementary, precooked cereal-based infant foods, powdered milk, and other dry beverage products made for reconstitution that are packaged, stored, and prepared in a way that maximizes retention of this vitamin. The consumption of natural sources of Vitamin C (fruits and vegetables) with iron-fortified dry blended foods is also recommended. Encapsulation can mitigate some of the AA losses during processing and storage, but these interventions will also add cost. In addition, the bioavailability of encapsulated iron in the presence/absence of AA will need careful assessment in human clinical trials. The long-term effect of high AA intake on iron status may be less than predicted from single meal studies. The hypothesis that an overall increase of dietary AA intake, or fortification of some foods commonly consumed with the main meal with AA alone, may be as effective as the fortification of the same food vehicle with AA and iron, merits further investigation. This must involve the consideration of practicalities of implementation. To date, programs based on iron and AA fortification of infant formulas and cow's milk provide the strongest evidence for the efficacy of AA fortification. Present results suggest that the effect of organic acids, as measured by in vitro and in vivo methods, is dependent on the source of iron, the type and concentration of organic acid, pH, processing methods, and the food matrix. The iron absorption-enhancing effect of AA is more potent than that of other organic acids due to its ability to reduce ferric to ferrous iron. Based on the limited data available, other organic acids may only be effective at ratios of acid to iron in excess of 100 molar. This would translate into the minimum presence/addition of 1 g citric acid to a meal containing 3 mg iron. Further characterization of the effectiveness of various organic acids in promoting iron absorption is required, in particular with respect to the optimal molar ratio of organic acid to iron, and associated feasibility for food application purposes. The suggested amount of any organic acid required to produce a nutritional benefit will result in unwanted organoleptic changes in most foods, thus limiting its application to a small number of food vehicles (e.g., condiments, beverages). However, fermented foods that already contain high levels of organic acid may be suitable iron fortification vehicles.

Absorption↗
PubMed2001

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function.

1. Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies. 2. Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat. 3. Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED(50) of 0.04 mg kg(-1). Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 - 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (-94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats. 4. Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would.

Animals↗
PubMed2001

Fatty acid absorption in preterms on formulas with and without long-chain polyunsaturated fatty acids and in terms on formulas without these added.

BACKGROUND/OBJECTIVE: Long chain polyunsaturated fatty acids have beneficial effects in preterm neurophysiological development and are semi-essential. Their levels and variation in plasma and red cells in term and preterms are better known than their intestinal absorption. In this paper the absorption of supplemented arachidonic acid (AA) and docosahexaenoic acid (DHA) is evaluated in a preterm group. DESIGN: Four newborn randomized groups were studied. Group T comprised 11 terms on regular formula. Preterms: group P (n=9) was on a classic preterm formula. INTERVENTION: groups PA (n=9) and PB (n=13) were on the same formula but PB contained AA and DHA in similar proportion to breast milk. At 20 days a 3 day metabolic balance was taken for Ca, P(i), Mg, total fat and individual fatty acids (C8-C24, saturated unsaturated). RESULTS: Calcium absorption was (mean+/-s.d.) 51+/-13% in terms. In preterms it was respectively 45+/-18, 38+/-11 and 37+/-21%. Total fat absorption was 92.0+/-8.0% in terms, and from 95.0+/-2.0 to 91.0+/-8.0% in preterms. Absorption of 8:0, 10:0 and 12:0 showed a very high and constant rate despite significant intake differences (715-33 mg/kg/day). Linoleic acid and alpha-linolenic acid were absorbed in the three groups at around 94% regardless of a greater LA intake in group P. Details of absorption (mg/kg/day) were: for AA, intake 17+/-7, fecal excretion 5+/-4, net retention 12+/-5 (75.0+/-18%); for DHA, intake 10+/-3, fecal excretion 3+/-2, net retention 6+/-4 (62.3+/-30%). CONCLUSION: Intestinal absorption of fatty acids is high and is comparable in terms and preterms as regards the studied acids. Longer acids were less well absorbed. The supplemented amounts of AA and DHA were less well absorbed and probably not impairing calcium absorption. SPONSORSHIP: University of Alicante, University of Miguel Hernández.

Arachidonic Acid↗
PubMed2002

Endocytosis by absorptive cells in the middle segment of the suckling rat small intestine.

In neonatal suckling rats, the absorptive cells of the duodenum, jejunum and ileum endocytose maternal milk macromolecules, including antibodies from the lumen. To determine whether the absorptive cells from the middle segment of small intestine have an apical endocytic membrane system that is the same as that of the duodenum, jejunum or ileum, we applied horseradish peroxidase by intraluminal injection, and examined the absorptive cells using light and transmission electron microscopy. In the middle segment of the small intestine, the absorptive cells had an apical endocytic membrane system including apical coated pits, apical invaginations, coated vesicles, vesicles, tubules, early endosomes, late endosomes and a large homogeneous electron-dense lysosome at the supranuclear region. This would suggest that the endocytic membrane system in the absorptive cells from the middle segment of the small intestine is specialized for quick and active intracellular digestion. The apical endocytic membrane system of the absorptive cells varied according to the segment of the small intestine, and the absorptive cells made their transition gradually from jejunal type to middle type, and then from middle type to ileal type at the suckling stage. The jejunal and ileal type of absorptive cells increased with growth, in contrast to the middle type.

Animals↗
PubMed2003

Effect of Tin-mesoporphyrin, an inhibitor of haem catabolism, on intestinal iron absorption.

Haem biosynthesis is the most important destination for absorbed iron, hence it can be hypothesized that iron absorption regulation should be integrated with haem metabolism. As an initial step to test this hypothesis, the effect on iron absorption of Tin-mesoporphyrin (SnMP), inhibitor of haem oxygenase, altering haem and its biosynthetic intermediates, was studied. Mice injected with SnMP (5-25 micro mol/kg daily for up to 3 d) showed dose-dependent increases in intestinal iron absorption measured in vivo and in vitro. In order to investigate the effects of SnMP, enzymes and intermediates of haem metabolism were measured. Hepatic 5-amino-laevulinate (ALA) synthase activity (pmol/min/mg protein) was significantly reduced in SnMP-treated mice (10 and 25 micro mol/kg daily for 3 d) (mean +/- standard deviation, control 11.2 +/- 2.6; treated 6.3 +/- 1.7; P < 0.01). Hepatic ALA dehydratase activity (pmol porphobilinogen/mg protein/min) showed significant reductions following SnMP treatment (control 180 +/- 60, treated 130 +/- 50; P < 0.05). The effect of SnMP on iron absorption was reversible, with absorption returning to normal after 3 d. Furthermore, the effect of SnMP on duodenal iron absorption was abolished by the simultaneous injection of ALA (6 micro mol/l). ALA alone had no effect on iron absorption. In-vitro studies using duodenal fragments isolated from mice treated with SnMP (10 micro mol/kg daily for 3 d), showed significant increases (P < 0.05) in both mucosal iron uptake and Fe(III) reducing activity. We conclude that intermediates in haem metabolism, in particular levels of ALA, may play a role in duodenal iron absorption.

5-Aminolevulinate Synthetase↗
PubMed1998

Intestinal calcium absorption in men with spinal osteoporosis.

OBJECTIVE: To investigate the role of serum 1,25-dihydroxyvitamin D (1,25D) in the decreased calcium absorption found in men with osteoporosis. DESIGN: Prospective study of patients referred to a university teaching hospital clinic for investigation of possible osteoporosis. PATIENTS: Male patients referred for investigation for osteoporosis, from 1981 to 1995, because of specific risk factors or radiological suspicion of osteoporosis. Men with vertebral compression fractures were compared with those without. MEASUREMENTS: Height and weight, radiocalcium absorption, serum 1,25D and fasting urinary calcium and hydroxyproline excretion. RESULTS: The men with vertebral fractures had higher fasting urinary hydroxyproline excretion (P = 0.003) and lower calcium absorption (P = 0.002) than the men without. Calcium absorption was positively related to 1,25D in both groups but the estimated calcium absorption at zero 1,25D was lower in the osteoporotic than the normal group. 1,25D was lower in the osteoporotic group than in the normal group. However this difference could only explain about half of the difference in calcium absorption between the groups. CONCLUSIONS: Calcium absorption is low in men with osteoporosis. About half of the deficit is due to low serum 1,25-dihydroxy vitamin D levels but there appears, in addition, to be some intestinal resistance to its effect on calcium absorption.

Adult↗
PubMed2003

Differential effects of metformin on bile salt absorption from the jejunum and ileum.

AIMS: The antidiabetic drug metformin is often associated with a small reduction in total circulating cholesterol, but the mechanism responsible is unknown. As bile salts contribute significantly to cholesterol homeostasis, this study has investigated the effect of metformin on the absorption of bile salts by the jejunum and ileum, and their transfer into bile. METHODS: Sodium-[1-14C]-glycocholate was administered into the jejunum or ileum of anaesthetized rats with and without metformin (250 mg/kg). Appearance of 14C-glycocholate in plasma and bile was followed for 150 min. RESULTS: Absorption of 14C-glycocholate from the ileum, which is a high-capacity active process, was 10-fold greater than absorption from the jejunum, which is mainly a passive process. Metformin increased threefold the absorption of 14C-glycocholate from the jejunum. Metformin similarly increased the appearance of jejunal 14C-glycocholate in plasma and bile. In contrast to the jejunum, absorption of 14C-glycocholate from the ileum was suppressed by more than half with metformin. This was associated with corresponding reductions of 14C-glycocholate in plasma and bile. DISCUSSION: Thus, metformin induced a large suppression of active bile salt absorption from the ileum compared with a small increase in passive absorption from the jejunum. This suggests that the ileal effect of metformin to reduce overall bile salt absorption could contribute to the modest cholesterol-lowering effect of this drug.

Animals↗
PubMed2001

Enhancement of jejunal absorption of conjugated bile acid by neurotensin in rats.

BACKGROUND & AIMS: Release of neurotensin (NT) from intestines is markedly stimulated by ingested fat, and NT may facilitate lipid digestion and absorption through various actions that are not fully understood. Our recent finding that NT stimulates hepatic output of bile acids only when bile delivery to the intestine is maintained has led us to investigate the effects of NT on bile acid absorption in the rat small intestine. METHODS: We measured the effects of intravenous infusion of NT (3-10 pmol x kg(-1) x min(-1)) on biliary recovery of (3)H-taurocholate ((3)H-TC) and (3)H-cholate administered into proximal and distal intestines or into isolated intestinal segments in situ in biliary fistula rats. To further understand the underlying mechanisms involved, the effects of NT on intestinal absorption of (3)H-D-glucose, (3)H-leucine, (14)C-antipyrine, and (51)Cr-EDTA were investigated by monitoring the absorption of radioactivity into superior mesenteric venous blood. RESULTS: Infusion of NT, at doses that caused near physiologic increases in blood NT levels, increased biliary recovery of (3)H-TC from the jejunum (3.4-fold) and ileum (1.7-fold), but did not enhance absorption of (3)H-cholate. NT also facilitated transcellular uptake of (3)H-glucose and (3)H-leucine and increased paracellular uptake to (51)Cr-EDTA and (3)H-mannitol, but did not alter the absorption rate for (14)C-antipyrine. CONCLUSIONS: These results indicate that NT can exert a facilitative effect on intestinal bile acid absorption and return to liver. This effect of NT may involve increases in paracellular absorption and carrier-mediated transport by mechanisms not yet identified.

Animals↗
PubMed2003

Fat-free foods supplemented with soy stanol-lecithin powder reduce cholesterol absorption and LDL cholesterol.

OBJECTIVE: The objective of this work was to show that fat-free, lecithin-formulated soy stanols lower cholesterol absorption and serum LDL cholesterol. DESIGN: Reduction in cholesterol absorption was measured in paired single-meal tests with or without formulated soy stanols (acute test), and changes in serum lipids were investigated in a 10-week, randomized, double-blind parallel trial in which formulated stanols or lecithin vehicle were given three times daily for the last 4 weeks (chronic test). SUBJECTS/SETTING: Forty-five normal or mildly hypercholesterolemic subjects were recruited for both studies. The 21 subjects (16 female, 5 male; mean age 32.5 years) in the absorption studies had the following mean lipid values: LDL cholesterol, 2.79 mmol/L and total cholesterol, 4.73 mmol/L. For the lipid reduction, 24 subjects (16 female, 8 male; mean age 50.6 years) were enrolled with mean LDL cholesterol and total cholesterol of 3.72 mmol/L and 5.66 mmol/L, respectively. INTERVENTION: Reduction in cholesterol absorption was measured using a lemonade beverage or egg whites that contained 625 mg stanols. Throughout the chronic study, subjects followed the American Heart Association Step I diet. During the 4-week treatment phase, subjects consumed daily a lemonade-flavored beverage containing either placebo or formulated soy stanols (1.9 g). MAIN OUTCOME MEASURES: Inhibition of cholesterol absorption was determined from the difference in plasma deuterated cholesterol enrichment after a test meal containing stanol-lecithin and one with lecithin vehicle only. In the chronic study, the primary endpoints were changes in LDL and total cholesterol. STATISTICAL ANALYSES PERFORMED: Paired or unpaired t tests were used to determine statistical significance. RESULTS: Stanol-lecithin reduced cholesterol absorption by 32.1% (P=.0045, n=10) and by 38.2% (P=.0022, n=11) when delivered in a lemonade-flavored beverage and in egg whites, respectively. Reduction in cholesterol absorption was strongly related to the initial level of absorbed cholesterol tracer in serum (r(s)=-0.739). Stanol-lecithin given in a beverage reduced total serum cholesterol by 10.1% (P=.0019, n=24) and LDL cholesterol by 14.3% (P=.0016, n=24). APPLICATIONS/CONCLUSIONS: Powdered soy stanol-lecithin lowers cholesterol absorption and LDL cholesterol when consumed in fat-free foods.

Adult↗