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PubMed1995

Iron absorption from the whole diet. Relation to meal composition, iron requirements and iron stores.

OBJECTIVE: To validate a new method of measuring iron absorption from the whole diet over several days, to compare iron absorption from two types of diets and to relate iron absorption to iron requirements and iron stores. DESIGN: Iron absorption from two diets was studied in 21 healthy young women. All non-haem iron in all meals was labelled to the same specific activity with an extrinsic radio-labelled iron tracer. Haem iron absorption was calculated from the amount of haem iron and absorption from a reference dose of iron. RESULTS: Iron absorption was concordant with individual iron requirements measured from menstrual blood losses and body weights. Total iron absorption from one diet designed to be highly bioavailable, would cover iron requirements in about 94% of menstruating women. Iron absorption was reduced by half from a diet with less meat, more phytate and more calcium with main meals. This type of diet would cover iron requirements in only 65% of adult menstruating women. For both diets there was a marked reduction in iron absorption with increasing serum ferritin. Iron balance was not positive above a serum ferritin of about 60 micrograms/l. CONCLUSIONS: Bioavailability of dietary iron is a key factor in iron nutrition. A diet with much lean meat, ascorbic acid and a low phytate content can cover iron requirements in most non-pregnant women. The powerful control of iron absorption implies that dietary iron overload cannot develop in normal subjects, even with diets having high iron content or high bioavailability.

Adult↗

PubMedDate not supplied

Mechanisms and regulation of intestinal iron absorption.

Iron absorption from the small intestine is regulated according to the body's needs, increasing in iron deficiency and decreasing in iron overload. It has been proposed that the efficiency of absorption is determined by the amount of iron acquired by developing enterocytes when they are in the crypts of Lieberkůhn and that this regulates expression of iron transporters such as DMT1 in mature enterocytes of the intestinal villi. In the crypts the cells take up iron from plasma transferrin by receptor-mediated endocytosis, a process that is influenced by the hemochromatosis protein, HFE. Hence, the availability of plasma transferrin-bound iron and the expression and function of transferrin receptors (TfR1), HFE and DMT1 should all contribute to the absorptive capacity of villus enterocytes. These aspects of the regulation and mechanism of iron absorption were investigated in genetically normal rats and mice, and in Belgrade anemic (b/b) rats and HFE knockout mice. In most experiments the function of the TfR1 was assessed by the uptake of radiolabeled transferrin-bound iron given intravenously. Absorption of non-heme iron was measured using closed in situ duodenal loops. The expression and cellular distribution of DMT1 and TfR1 were determined by in situ hybridisation and immunohistochemistry. The uptake of transferrin-bound iron and expression of functional TfR1 was shown to occur mainly in crypt cells and to be proportional to the plasma concentration of iron. It was not impaired by the mutation of DMT1 that occurs in b/b rats but was impaired in HFE knockout mice. Iron absorption was increased in these mice but was still influenced by the level of iron stores, as in normal mice. These results are in accordance with the proposed regulation of iron absorption and suggest that DMT1 is not the only iron transporter operating within endosomes of crypt cells. This view was supported by the failure to detect DMT1 mRNA or protein in crypt cells. Expression of DMT1 mRNA and protein started at the crypt-villus junction and increased to reach highest levels in the mid-villus region. Greater expression was found in iron deficiency and less in iron loaded animals than in controls and in the iron deficient rats most of the protein was present on the brush border membrane. In normal rats the efficiency of iron absorption parallelled the level of DMT1 expression, but in b/b rats absorption was very low and independent of dietary iron content even though DMT1 was present in villus enterocytes. The results confirm the essential role of DMT1 in the uptake phase of non-heme iron absorption. When normal rats previously fed a low iron diet were given a bolus of iron by stomach tube, the subsequent absorption of iron from a test dose placed in the duodenum diminished in parallel with the expression of DMT1 mRNA and protein, commencing within 1hour and reaching low levels by 7 hours. The margination of DMT1 to the brush border membrane disappeared. These results show the level of expression and intracellular distribution and function of DMT1 respond very quickly to the iron content of the diet as well as being affected by storage iron levels.

Anemia↗

PubMed1998

Buccal absorption of enalapril and lisinopril.

OBJECTIVE: The buccal absorption of captopril does not exhibit the classical pH/partition hypothesis, suggesting that mechanisms other than passive diffusion are involved in its absorption; animal studies have suggested that a peptide carrier-mediated transport system may be responsible for its absorption. The present study evaluated the effects of pH on octanol partitioning, and on the buccal absorption of enalapril and lisinopril, using in vitro techniques and buccal partitioning in human volunteer subjects. METHODS: The partitioning of enalapril and lisinopril into n-octanol was examined over the pH range of 3 9 at room temperature. RESULTS: Enalapril exhibited maximal partitioning into the organic phase at pH 4 5; minimal partitioning was recorded at pH values 8 and 9. The partitioning of lisinopril into n-octanol was found to be maximal at pH 9 and minimal at pH 3. Using the buccal absorption technique, the partitioning of enalapril and lisinopril (0.5 mg), was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8 and 9). In the case of enalapril, lowest buccal partitioning occurred at pH 3, 8 and 9, while maximal partitioning occurred at pH 5; absorption of lisinopril was not extensive at any pH, but was greatest at pH 6. These results, in addition to the n-octanol partition coefficients, indicated that enalapril obeyed the normal lipid partition hypothesis with respect to buccal absorption. The buccal absorption of lisinopril also obeyed the lipid partition hypothesis over the pH range 3-7. These findings are in direct contrast to those for captopril. The buccal partitioning experiments were repeated at the maximal pH for absorption for each angiotensin converting enzyme (ACE) inhibitor, but with the addition of cephradine (0.05 mmol x l(-1)). CONCLUSION: The data indicated that the presence of this peptide transport inhibitor had no effect on the buccal absorption of enalapril (0.06 mmol x l(-1)) and lisinopril (0.057 mmol x l(-1)), which suggests that both drugs do not share a common buccal absorption pathway with cephradine.

Administration, Buccal↗

PubMed1985

Importance of Environmental pH during Root Development on Phosphate Absorption.

Wheat seedlings (Triticum aestivum L. cv Gamenya) were grown for 4 days in culture solutions of differing pH prior to studying their subsequent short-term absorption of (32)Pi from solutions of the same or different pH.Increasing pH of the absorption solution from 5.5 to 7.0 or 8.0 depressed (32)Pi absorption from 1 and 10 micromolar Pi but had little effect at 100 and 1000 micromolar Pi. Increasing the pH of the culture solution from 4.5 to 6.5 doubled or trebled subsequent (32)Pi absorption from nearly all absorption solutions over a wide range of Pi concentrations, pH, and nutrient compositions.When seedlings were transferred between culture pH treatments 4.5 and 6.5, their capacity for (32)Pi absorption remained unchanged for at least 5 hours and adjusted by 60 to 80% after 24 hours and completely after 48 hours. This suggests that the root's capacity to absorb Pi responds to pH through slow structural changes in its mechanism of Pi absorption. P content and concentration of wheat seedlings reflected the response of (32)Pi absorption to culture pH.It is suggested that absorption pH affects an activity component of the process for Pi absorption and culture pH affects a capacity component. Failure to recognize the capacity component of the pH response explains why previously published results for short-term (32)Pi absorption conflict with those for long-term P accumulation in plants.

Journal Article↗

PubMed1993

Influence of gastric acidity on fluoride absorption in rats.

The rate of F absorption from the stomach is pH-dependent, with greater absorption at low pH. Since the rate of absorption is also strongly influenced by the rapidity of gastric emptying, we have compared the relative importance of gastric acidity and gastric emptying in overall F absorption. Male rats (350 g, n = 85) were pre-treated with cimetidine (to inhibit gastric acid secretion) or pentagastrin (to stimulate gastric acid secretion) or were untreated controls, and given 50 micrograms F by stomach intubation. The pH of the F-containing solution was varied in the cimetidine-pre-treated group (pH 1.5, 5.5, 8.5), and was 5.5 for the control and pentagastrin-pre-treated groups. Gastric emptying was measured by addition of 14C polyethylene glycol to the F solution as an unabsorbed marker of fluid movement. F absorption was measured after 10, 20, and 40 min. The rate of gastric emptying was unaffected by pre-treatment or pH of the intubating solution. Initially, F absorption was greatest at low pH. After 40 min, absorption was comparable in all groups, averaging approximately 70% of the initial dose. The extent of absorption from the stomach was inversely related to pH, but increased absorption from the small intestine compensated for the low gastric absorption at high pH.

Absorption↗

PubMed2001

Absorption of 193- and 213-nm laser wavelengths in sodium chloride solution and balanced salt solution.

OBJECTIVE: To determine absorption coefficients for sodium chloride solution (saline) and balanced salt solution at the 193- and 213-nm laser wavelengths. METHODS: Absorption coefficients were obtained for each of the component species found in balanced salt solution. This was achieved by measuring laser pulse transmission through solutions of varying concentration. The experiments were repeated using the 193-nm excimer and 213-nm solid-state laser wavelengths. Results for each species were then used to obtain an overall absorption coefficient and penetration depth for balanced salt solution and 0.9% sodium chloride solution. RESULTS: Absorption coefficients in balanced salt solution for the 193- and 213-nm wavelengths were found to be 140 and 6.9 cm(-1), respectively. In 0.9% sodium chloride solution, the absorption coefficient was 81 cm(-1) at 193 nm and 0.05 cm(-1) at 213 nm. At 193 nm, absorption in balanced salt solution was dominated by sodium chloride. Sodium citrate emerged as the dominant species of absorption at 213 nm. CONCLUSIONS: For the species investigated, we found reduced absorption for the longer wavelength of 213 nm. While the difference in wavelength between 193 and 213 nm is within about 10%, the respective molar absorption coefficients varied by 1 to 4 orders of magnitude. This indicates that predictions for the wavelength-dependent changes of absorption coefficients of other solutions are unreliable. CLINICAL RELEVANCE: Fluid placed on the surface of the cornea during keratorefractive surgery has proved to be a barrier to ablation for the 193-nm wavelength. The increased penetration depth through sodium chloride solution and balanced salt solution for the longer 213-nm laser wavelength may mean that these solutions cannot be used as a masking agent for keratorefractive procedures performed with this wavelength.

Absorption↗

PubMed1978

Effect of a single ingestion of alcohol on iron absorption.

The effect of alcohol on inorganic and organic iron absorption was studied in 70 subjects, using a whole-body counter technique. The mean iron absorption of a test dose was 24.44%, while in the presence of whisky, absorption fell to 9.73% (P less than 0.0001). Absorption of a test dose in the presence of whisky without alcohol was 10.14% (P less than 0.0001). The alcohol in whisky, therefore, was not responsible for the diminished iron absorption (P greater than 0.20). The absorption of the iron contained in wine with alcohol was 73.31 microgram and wine without alcohol was 67.50 microgram. The difference was not statistically significant (P greater than 0.20). The absorption of inorganic iron contained in a test meal was 165.55 microgram and was not changed in the presence of ethanol (151.35 microgram) (P greater than 0.10). However, the presence of ethanol affected the absorption of heme iron: 538.68 microgram compared with 442.41 microgram with ethanol (P less than 0.0001). These studies show that the acute ingestion of ethanol does not influence the absorption of inorganic iron, while it does diminish the absorption of the organic form.

Absorption↗

PubMed1991

Characterization of ethiofos absorption in the rat small intestine.

The absorption characteristics of ethiofos were studied using the rat in situ intestine circulating perfusion technique. Slow absorption kinetics were observed for ethiofos with varying rates of absorption and metabolism/degradation in situ as a function of buffer and absorption enhancers. In most cases less than 10 per cent of the radiolabeled compound is lost from the circulating perfusate in 90 min. In addition, over the same time period greater than 40 per cent of the intact parent compound was lost by degradation. Much of the difference can be accounted for in the formation of the free thiol metabolite. WR-1065, suggesting ester hydrolysis or metabolic activity. Good stability was observed in all perfusate systems ex vivo indicating that the degradation occurs in situ. The disodium salt of ethylenediaminetetraacetic acid (EDTA) was shown to be an effective absorption enhancer of ethiofos. The enhancement of intestinal absorption by EDTA was dose-dependent resulting in a 20-fold increase in blood levels of ethiofos in the portal blood. Follow-up studies in the rhesus monkey confirm this observation. Salicylate and dimethylsulfoxide (DMSO) also resulted in absorption enhancement although to a lesser degree than that seen after EDTA treatment. Addition of several alkaline phosphatase inhibitors did not significantly improve absorption of ethiofos in the rat small intestine. Proposed mechanism(s) for intestinal absorption and absorption enhancement of ethiofos are discussed.

Alkaline Phosphatase↗

PubMed1990

Absorption characteristics of a new valproate formulation: divalproex sodium-coated particles in capsules (Depakote Sprinkle).

To determine the absorption characteristics of a new dosage form of divalproex sodium consisting of coated particles in a pull-apart capsule (Depakote Sprinkle, Abbott Laboratories, North Chicago, IL), two absorption studies were conducted in adult volunteers. Ten fasting men participated in a single-dose, crossover study comparing absorption from Sprinkle capsules versus enteric-coated tablets (study 1). Eleven men participated in a multidose study (study 2) in which Sprinkle capsules or enteric-coated tablets were given once every 24 hours for three doses under fasting and nonfasting conditions. In study 1, the extent of absorption from Sprinkle capsules equalled that from enteric-coated tablets. Compared to enteric-coated tablets, Sprinkle capsules had earlier absorption onset, 1 versus 2.6 hours (P less than .05), slightly slower absorption rate, time to reach peak (tmax) of 4.0 versus 3.4 hours (P less than .1), and lower maximum peak plasma drug concentration (Cmax), 20.7 versus 25.9 mcg/mL (P less than .05). In study 2, food intake did not affect onset or extent of absorption nor maximum concentration, but did slow rate of absorption. Time to reach peak concentration was 2.7 hours for tablet (fasting), 3.3 hours for capsule (fasting), and 4.8 hours for capsule (nonfasting) (P less than .05). Intrasubject absorption performance from the three doses was highly consistent, regardless of food intake. These data indicate that Sprinkle capsules possess desirable absorption characteristics in a form that makes ingestion easier for patients who have difficulty taking other valproate dosage forms.

Adolescent↗

PubMed2002

Solute disposition in the rat lung in vivo and in vitro: determining regional absorption kinetics in the presence of mucociliary escalator.

Solute absorption from the airways was compared and modeled in vivo and in vitro isolated perfused rat lung (IPRL), and its regional kinetic descriptors in the presence of competing mucociliary escalator were estimated. 7.4 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA), FITC-labeled dextran 40 (FD-4) and sodium fluorescein (F-Na) were used as model solutes. They were reproducibly administered into the airways in a range of doses in vivo and in vitro IPRL, and their initial deposition and subsequent absorption profiles compared. Each of the absorption data was fitted across doses to a kinetic model in which rate constants for Michaelis-Menten-type active (V(max,P) and K(m,P)) and/or first-order passive (k(a,P)) absorption and mucociliary escalator (k(E)) were estimated simultaneously. Statistically indistinguishable initial solute distribution was ensured in vivo and in vitro. The absorption profiles for F-PHEA were kinetically identical in vivo and in vitro, and their modeling analysis revealed the presence of competing, solute-independent pulmonary-to-bronchial mucociliary escalator with a half-life of 28.9 min. F-PHEA's active absorption was found to be 77 times faster than its passive absorption, yet this was present only in the pulmonary region. Passive solute absorption was inversely related to solute molecular weight [F-PHEA < FD-4 < F-Na]. Bronchial absorption was shown for F-Na in vivo and its rate indistinguishable from that from the pulmonary region. Thus, a single kinetic model was developed, enabling regional absorption kinetic analysis both in vivo and in vitro, in the presence of competing, solute-independent mucociliary escalator.

Absorption↗

PubMed1975

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↗

PubMed1976

Pulmonary absorption studies utilizing in situ rat lung model: designing dosage regimen for bronchial delivery of new drug entities.

The absorption of 7-methylsulfinylxanthone-2-carboxylic acid, 7-(methylthio)xanthone-2-carboxylic acid, and their sodium salts from the respiratory tract of anesthetized rats was studied after intratracheal administration of 0.1 ml of a solution or suspension containing the drug. At various times after administration, the lungs and trachea were removed and assayed radiochemically for unabsorbed drug. Sodium 7-(methylthio)xanthone-2-carboxylate from solution was absorbed approximately 20 times faster than sodium 7-methylsulfinylxanthone-2-carboxylate from a solution. The absorption from solutions was three to four times faster than the absorption from suspensions. For inhalation aerosol dosage forms intended for prophylactic use, the drug entity with slower systemic absorption probably would be more desirable than the drug entity with rapid absorption. Rapid systemic absorption following inhalation of powder or liquid aerosols would lead to more frequent dosing if the biological activity is related to the drug concentration in the tracheobronchial tissues. Therefore, the powder or liquid inhalation aerosols of organic acids rather than the corresponding sodium salts may be preferable for designing a dosage regimen. However, if the dosage form is intended for utilizing the bronchodilator activity of the compound, the drug entity with rapid absorption is more desirable. Therefore, in the treatment of asthmatic attacks, liquid or powder inhalation aerosols of the sodium salt of the rapidly absorbing drug entity are preferable. The absorption rates were directly proportional to concentration when the initial concentration of sodium 7-methylsulfinylxanthone-2-carboxylate was varied over a 333-fold range. The effect of the pH of the drug solution administered intratracheally to the rat lung indicated a sharp increase in the pulmonary absorption at a pH near the pKa. The results suggested that structurally related xanthones are absorbed possibly by passive diffusion across the lipoidal region of the pulmonary membranes and that the absorption of organic acids and organic electrolytes is mainly controlled by the lipid solubility of the unionized species.

Absorption↗

PubMed1981

Chronic dog intestinal loop model for studying drug absorption as exemplified by beta-adrenoreceptor blocking agents, atenolol and propranolol.

Chronic in situ loops of dog small intestine (jejunum or ileum) were used to investigate the absorption of the beta-adrenoreceptor blocking agents atenolol and propranolol. Absorption measurements were made in conscious dogs by monitoring drug disappearance from solution in the loop, with correction for intestinal water absorption. The jejunum had a mean resting pH of 7.3 and a slight net secretion of water into the lumen; the ileum had a resting pH of 7.9 and a strong net absorption of water. Propranolol absorption was rapid and first order in both regions, with the ileum showing faster absorption than the jejunum due to its higher resting pH. In contrast, atenolol absorption was negligible in the jejunum and only moderate in the ileum. The data were quantitatively consistent with the pH-partition mechanism for the absorption of propranolol but not for atenolol. The model was validated for atenolol by showing that, following drug administration into jejunal and ileal loops, drug disappearance rates were similar to absorption rates calculated from systemic blood levels. This technique is useful, realistic, and relatively simple for studying intestinal drug absorption without seriously perturbing normal GI conditions.

Animals↗

PubMed1986

Simultaneous first- and zero-order absorption of carbamazepine tablets in humans.

The absorption kinetics of carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) in healthy adult volunteers was investigated following a single 400-mg (2 X 200-mg) oral dose of commercially available conventional tablets (Tegretol). Wagner-Nelson plots of the data from all subjects (n = 10) showed that the fraction remaining to be absorbed declined in a biphasic manner, suggesting a mixed order of absorption. A model assuming the absorption of carbamazepine by simultaneous first-order and zero-order rates was used to describe the overall absorption process. Model parameters (and their mean +/- SD values) were: alpha, the fraction of the dose absorbed at a first-order rate (0.646 +/- 0.070); Ka, the first-order absorption rate constant (0.45 +/- 0.13 h-1); and tdur, the duration of the zero-order absorption component (36.0 +/- 4.4 h). If complete absorption can be assumed, then the corresponding average zero-order rate was 4.0 mg X h-1. The results indicate that 35% of the available dose is absorbed at a zero-order rate. These data suggest a prolonged constant rate of absorption due to continued delivery during its transit in the intestine. In addition, an assessment of the mean absorption time, based on the parameters from the model described above, compared closely (7.95 versus 8.44 h) with the mean absorption time estimated from an analysis of the fraction remaining to be absorbed versus time plot using a noncompartmental approach.

Adult↗

PubMed1990

Effect of medium-chain glycerides on the intestinal absorption of phenol red: studies on mechanisms of the promoting effect.

To elucidate the mechanisms of the promoting action of medium-chain glyceride (MCG) on the intestinal absorption of phenol red (PR), the effect of different MCG dose levels on PR absorption, the absorption kinetics of MCG itself, and the mucosal reduced glutathione (GSH) levels were investigated to determine whether or not they are related to the promoting action of MCG. The absorption of PR was found to be enhanced with an increase in MCG dose (as an emulsion in the range 0.5-4.0%). Urinary excretion of PR was reduced by absorbed MCG components, which also resulted in an increase in the AUC. Moment analysis of plasma PR concentrations after intraintestinal administration revealed a shorter mean absorption time (MAT) for the emulsion formulation than for the control. The mucosal GSH level was lowered by the administration of the MCG emulsion (2-10%) into the intestinal lumen. Pretreatment with a 4% MCG emulsion decreased GSH levels to one-half of the control. In these cases, the level of mucosal GSH seemed to remain constant to the end of the experiment after it had decreased during the initial period. On the other hand, results from the in situ loop or recirculation study showed that enhancement of PR absorption appeared in the earlier period and then gradually decreased. The time course of the PR absorption rate, estimated from plasma concentration data, was similar to that of the MCG absorption rate. These results suggest that the promotion of intestinal absorption is related to the absorption kinetics of MCG itself, but not directly to the level of mucosal GSH.

Animals↗

PubMed1992

Rate-limiting steps in oral absorption of a leucotriene D4 antagonist in the beagle dog.

Oral administration of a leucotriene D4 antagonist drug (1) in the Beagle dog at doses of 2, 20, 100, 300, and 800 mg/kg resulted in dose-dependent bioavailability values (4-50%). To understand the dose dependence of the absorption of 1 in the dog, initial rates of absorption of 1, which were estimated from Loo-Riegelman analysis of the concentration in blood data, were analyzed in terms of dissolution and absorption rates. From the Loo-Riegelman plots, the initial rates of absorption of 1 were estimated as 8.2, 41.9, 41.1, 76.1, and 72.8 micrograms.mL-1.h-1, respectively, for the doses given earlier. These data, which indicate leveling of the initial absorption rates at high doses, were consistent with an absorption model in which the dissolution rate is the rate-controlling step in the intestinal absorption of 1 at doses less than 100 mg/kg. The powder dissolution rate of 1 in 17 mM bile salt solution was estimated as 14 and 700 micrograms.mL-1.h-1 for amounts of 1 equivalent to the amounts given to dogs at 2- and 100-mg/kg doses, respectively. After consideration of the volume of distribution and the volume of intestinal fluid in the dog, the value of the initial dissolution rate was much lower than the initial absorption rates at the 2-mg/kg dose. Oral administration of 1 at 2 mg/kg in a 3% polysorbate 80 solution enhanced both the rate and the extent of absorption of the compound. These results confirm the validity of the conclusion that the intestinal absorption of 1 is limited by dissolution rate at low doses.

Administration, Oral↗

PubMed1996

Amiloride inhibits meal-stimulated colonic absorption.

Meal-stimulated colonic absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purpose of this study was to determine the contribution of Na+ transport pathways to colonic proabsorption. Distal colonic Thiry-Vella loops were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing [14C] polyethylene glycol as the impermeant marker. In the first set of experiments, the dose dependence of amiloride-induced inhibition of basal colonic absorption was determined. In the second set of experiments the effect of amiloride, which inhibits both Na+ channels and Na+/H+ exchange in colonocytes, on meal-stimulated colonic absorption was determined. Luminal amiloride inhibited basal colonic absorption in a dose-dependent manner, with significant reductions in Na+ absorption occurring with concentrations of 10(-2)M and higher. Infusion with 10(-3)M amiloride, a concentration that did not alter basal absorption, resulted in significant reductions in postprandial water, Na+, and Cl- absorption. These results suggest that meal-stimulated colonic absorption is mediated, at last in part, by transcellular Na+ absorptive pathways.

Amiloride↗

PubMed1996

The use of mechanistically defined chemical mixtures (MDCM) to assess component effects on the percutaneous absorption and cutaneous disposition of topically exposed chemicals. I. Studies with parathion mixtures in isolated perfused porcine skin.

Recently, attention has been directed to the risk assessment of cutaneous exposure to chemical mixtures rather than to only a single compound since this is the exposure scenario in the environment, residence, and work place. Using acetone or dimethylsulfoxide (DMSO) (80% in water) as a vehicle, percutaneous absorption and cutaneous disposition of parathion (PA) were studied following PA (40 microg/cm2) dosing on isolated perfused porcine skin as mechanistically defined chemical mixtures (MDCM) consisting of the surfactant sodium lauryl sulfate (SLS), the rubefacient methyl nicotinate (MNA), and the reducing agent stannous chloride (SnCl2). A full 2 x 4 factorial design was used to asses treatment effects and potential interactions. More radiolabel was absorbed with DMSO than with acetone albeit an earlier peak flux time but lower peak flux was observed with acetone than with DMSO. The absorption flux rate profiles with DMSO continued increasing but bipeak-featured profiles were observed with acetone. SLS enhanced PA absorption with both DMSO and acetone. The presence of MNA in both vehicles blunted the absorption rate curves without significantly changing total absorption. SnCl2 blocked PA absorption and increased residue level on the skin surface and in the stratum corneum (SC). The venous flux profiles were mixture-dependent and highly reproducible within treatment groups. Higher level interactions were also noted. This study indicated multiple levels of interactive effects on PA absorption which must be incorporated into any effort to identify critical mechanisms which affect risk assessment of topically exposed mixtures. It was suggested that the chemicals selected in a topically applied mixture may have significant effects on the penetration/distribution pattern and percutaneous absorption profile of a toxicant/drug in the mixture. The MDCM approach may be useful in a screening or triage approach to identify mixture components which affect marker chemical absorption as well as identify potential mechanisms which deserve further attention. Risk assessment efforts could then be focused on those mixtures, containing these critical components, which would be expected to have the greatest penetration and absorption.

Animals↗