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Iron absorption from the whole diet, which contained a highly bioavailable form of iron, was measured for 5 d in 31 health men, including 12 blood donors. Nonheme iron in all meals was labeled with an extrinsic, inorganic radioiron tracer added in amounts to ensure uniform specific activity in all meals. Heme iron was labeled similarly by using hemoglobin biosynthetically labeled with another radioiron tracer. There was a good inverse relation between total absorption and concentration of serum ferritin up to approximately 60 micrograms/L. In subjects with serum ferritin > 60 micrograms/L there was no relation to iron absorption. At this serum ferritin concentration, absorption decreased to a level just sufficient to cover basal iron losses, implying that at a serum ferritin concentration > or = 60 micrograms/L no further accumulation of iron stores will occur by dietary iron absorption. The findings thus suggest that in normal subjects there is no risk of developing iron overload by iron absorption from the diet even if the diet is fortified. Similar findings were made previously in two studies in women, both of which indicated an effective control of absorption. At the same serum ferritin concentration the absorption per kilogram body weight was the same in men and women served identical diets with a high iron bioavailability. These new observations strongly suggest that translation of serum ferritin concentration into amounts of stored iron should be made with caution and that in subjects with high serum ferritin concentrations, other causes than increased iron stores should be considered. There was effective control of both heme- and nonheme-iron absorption but their relations to iron status were different.
The purpose of this study was to clarify the absorption characteristics of a drug across the mesenteric surface, which occupies a large area of absorption in the peritoneal cavity, in order to determine the drug absorption route after intraperitoneal administration. Absorption of phenolsulfonphthalein (PSP) as a model after application to the mesenteric surface was investigated in rats by employing a cylindrical diffusion cell attached to the mesentery with or without blood vessels. PSP was absorbed from the rat mesenteric surface, followed by its appearance in the plasma and bile, regardless of blood vessel existence. The absorption ratios of PSP in 6 h were calculated to be 92.1 and 83.6% from the mesenteric surface with and without blood vessels, respectively. We then employed an experimental system in which a polyethylene (PE) cap was stuck on the surface of the other side to exclude the influence of absorption of the drug from the other organ surfaces that penetrated across the mesentery. The PE cap decreased the appearance of PSP in the plasma from the mesenteric surface with blood vessels and eliminated the PSP absorption completely from the mesenteric surface without blood vessels. Accordingly, blood vessels on the mesenteric surface must actually play an important role in drug absorption, but the contribution of the mesenteric surface to drug absorption from the peritoneal cavity is unlikely to be significant because there is a small effective area of blood vessels.
In order to develop some oral drug preparations containing calcium salt of fosfomycin ((minus)-cis-1,2-epoxypropylphosphonic acid) which is a new antibiotic, the absorption, distribution and excretion were studied when it was administered orally to fasted test animals such as rats, rabbits and dogs. The results are as follows: 1) In the case of rats, the more dose size was increased, the more ratio of excretion in urine as index of gastrointestinal absorption was reduced and ratio of excretion in stools was adversely increased, which suggested a decrease in absorption efficiency. But, as absolute amount of excretion in urine became larger with dose size, it was considered that increase in dose size would serve for elevation of serum levels. 2) When the calcium salt was given to rats and rabbits in form of solution and suspension, the former was more eminent than the latter regarding to absorption efficiency, as generally known. The solution, however, needed relatively large quantity of water to solubilize the calcium salt, and it was not considered that the absorption efficiency depends on only dissolution step or dissolution rate. 3) Difference of the particle size varying from 1.50 mu(bulk particle size) and 0.64 mu(mechanical limit size) measured by Kozeny-Carman method did not affect on the absorption in rats and dogs. So it was considered that the bulk could be use directly without micronizing in manufacturing process for the oral preparations. 4) There were some differences of absorption among the animal species. Good absorption was shown in turn in rats, dogs and rabbits. These differences might depend not only on physiological factors but also anatomical differences such as length of gastrointestinal tract. 5) In rabbits high concentration was observed successively in kidney, lung, heart and so on. In any organ its level decreased similarly to the serum level, not sustaining its initial high concentration. The calcium salt did not possess any affinity to certain organs. 6) In conclusion, though some differences of gastrointestinal absorption were observed among the animal species, fosfomycin calcium salt was well absorbed without problem of micronizing the bulk particles. Moreover, it was perceived that fosfomycin calcium salt, once distributed, would not remain in particular organs, being excreted out of body.
The extent of absorption of sulfanilamide, bretylium tosylate, sulfisoxazole acetyl, and riboflavin was determined in rats exposed to 850 rad of cobalt-60 gamma-radiation of sham irradiated. The drug were administered orally at 1 or 5 days postirradiation, and the amount of drug excreted in the urine was used as the measure of absorption. Following intravenous drug administration, there was no difference between irradiated and control animals in the amount of drug excreted in the urine. At 1 day postirradiation, the absorption of sulfanilamide and bretylium was not affected by radiation; the absorption of sulfisoxazole acetyl and riboflavin was increased. The fraction of sulfanilamide excreted in the urine as N4-conjugate was increased at 1 day postirradiation. At 5 days postirradiation, there was no detectable difference between irradiated and control animals in the extent of drug absorption. The effects of radiation on the extent of absorption of orally administered drugs were most pronounced immediately following irradiation. Irradiation apparently does not affect the absorption of drugs that are normally well absorbed or poorly absorbed due to slow transport across the GI mucosa. Following irradiation, there may be an increase in the extent of absorption of drugs that are poorly absorbed due to low aqueous solubility or that are absorbed by a saturable transport mechanism.
We studied the potential of an animal model to predict nonheme iron absorption in humans and tested a feasible and easy technique of dosing 59Fe to evaluate bioavailability of dietary nonheme iron. Plant diets containing about 20 ppm or 75 ppm iron were the nonheme iron sources with ferrous sulfate (75 ppm) as a reference. Radioiron was administered by (a) gavaging in water, 1 h after a meal; (b) mixing with the meal; and (c) making a slurry with the meal and gavaging. No significant differences were found (P less than or equal to 0.05) in 59Fe absorption among the three methods of administering radioiron. Absorption of 59Fe was similar to apparent iron absorption for all diets tested, whether the animals consumed the same diet as that of the test meal or a different diet. A high correlation (r = 0.88) obtained between the apparent iron absorption and 59Fe iron absorption for different dosing techniques, indicates that extrinsic iron tag administered by any of these methods is valid to measure nonheme iron absorption. Apparent iron absorption values determined by rats fed 20 ppm or 75 ppm dietary iron from plant sources were similar to reported values for humans. It is concluded that the normal adult rat is an appropriate model to study iron bioavailability of human foods when iron status, maturity, iron intake relative to requirement, and method of measurement are similar to the human situation.
The purpose of this study was to characterize the rat jejunal passive transport and the possible active efflux of three local anaesthetics, ropivacaine, lidocaine and bupivacaine using two different absorption models, the in situ single-pass intestinal perfusion and the in vitro Ussing chamber model, as well as P-glycoprotein (Pgp)-mediated calcein transport inhibition in Caco-2 cells. Concentration and pH dependence, efflux inhibition by verapamil and digoxin and bi-directional permeability studies were performed to investigate the potential involvement of efflux carriers in the intestinal absorption of the local anaesthetics. In the jejunal perfusion the permeability of these agents appeared to be high, predicting complete intestinal absorption (>90%). There was no effect of the Pgp inhibitors on net absorption for any of the local anaesthetics in the two absorption models. However, in the Ussing chamber at an equal pH of 7.4 at mucosal and serosal sides, the observed jejunal permeability ratios (S-M)/(M-S), of 2.3, 1.8 and 3.0 for ropivacaine, lidocaine and bupivacaine, respectively, indicated at least some involvement of carrier-mediated intestinal secretion. This idea was supported in the calcein AM Pgp transport assay in which two of the tested local anaesthetic agents affected cellular calcein retention. As anticipated for these agents, the mucosal pH conditions were shown to largely affect the gut permeability. The jejunal permeabilities of the local anaesthetics as measured in the two absorption models fitted well in a model comparison that incorporated the permeabilities of six other structurally unrelated drugs. In conclusion, the jejunal permeability of ropivacaine, lidocaine and bupivacaine was high and although evidence was obtained for carrier-mediated intestinal efflux this process appeared not to have a significant influence on the rate and extent of in vivo intestinal absorption. Rather, passive diffusion of these agents seems to be the major mechanism for the intestinal absorption.
BACKGROUND AND AIMS: Plant sterols are widely distributed in human diet but are poorly absorbed so that their plasma levels are very low. However, when fed in large amounts, they lower plasma cholesterol levels by interfering with cholesterol absorption. We have studied the effect of 4 weeks of feeding a chow diet supplemented with 1% plant sterols [brassicasterol (6.3%), campesterol (28.5%), stigmasterol (15.6%) and sitosterol (49.6%)], with or without SCH 58235 (a derivative of ezetimibe), 30 mg/kg per day, known to suppress intestinal cholesterol absorption, on plasma, tissue, biliary, and fecal sterols in Wistar and wild-type Kyoto (WKY) rats, and their metabolism by intestinal bacteria. METHODS: After 2 weeks of feeding control or experimental diet, rats were given [3alpha-(3)H]sitosterol intravenously and [4-(14)C]sitosterol by mouth, and blood was collected after 1, 2, 3, and 5 days after labeling to determine sitosterol absorption. Feces were collected during the last 3 days and freeze dried. At the end of feeding, bile fistulas were created in 3 rats of each strain and bile was collected for 1 hour. All rats were then sacrificed and plasma and liver were collected for sterol measurements and activities of hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, and cholesterol 27-hydroxylase. RESULTS: Wild-type Kyoto rats were hypercholesterolemic compared to Wistar rats and had increased plant sterols in the plasma. Plasma cholesterol tended to be lower in WKY rats after feeding with plant sterol-enriched diet whereas plant sterol levels rose to approximately 31% of plasma sterols in WKY and 14% in Wistar rats. However, brassicasterol and stigmasterol, with a double bond at C-22, constituted less than 3.5% of total plasma plant sterols. After feeding, biliary plant sterols increased 2.25-fold in Wistar and 1.5-fold in WKY rats, suggesting less hepatic clearance in WKY rats. SCH 58235 feeding significantly increased plasma as well as biliary cholesterol levels in both the untreated and plant sterol-fed WKY rats, and the plasma plant sterols showed a tendency to increase but did not reach significant level. Intestinal bacteria in both rat strains metabolized all plant sterols to mainly the 5beta-H-stanols. However, the C-22 double bond was stable to bacterial degradation. Intestinal absorption of sitosterol and cholesterol was increased 1.5- and 1.3-fold, respectively, in the WKY rats as compared to the Wistar rats, and plant sterol feeding lowered absorption of these sterols in both strains. Absorption of both these sterols was also lowered in SCH 58235-treated rats in both strains and was further lowered when SCH 58235 and plant sterols were simultaneously fed. The activity of the rate-limiting enzyme, HMG-CoA reductase, was increased 1.57-fold in Wistar rats and 1.27-fold in WKY rats that were fed plant sterols as compared to untreated rats. CONCLUSIONS: (1) Plant sterol absorption was increased whereas hepatic elimination of all sterols was diminished in WKY rats accounting for elevated cholesterol and plant sterol levels. (2) The 1% plant sterol-enriched diet tended to lower plasma cholesterol levels whereas SCH 58235 feeding significantly increased plasma cholesterol levels in the WKY rats. (3) Intestinal absorption of sterols with C-22 double bond is diminished and the side-chain double bond is resistant to intestinal bacteria.
This study was designed to clarify whether the anti-absorptive action of prostaglandin E2 (PGE2) on glucose absorption was specific or non-specific to the glucose absorptive process, by investigating its effect on fructose absorption which has a different mechanism from that of glucose absorption. The effect of PGE2 on mucus secretion was also evaluated as one of the non-specific inhibiting factors. PGE2 significantly stimulated the secretion of water and mucus, and the absorptions of glucose and fructose were inhibited 49.3 per cent and 31.1 per cent respectively at the highest dose. However, fructose absorption was not inhibited by lower doses of PGE2, although the secretion of fluid and mucus was stimulated significantly and glucose absorption was inhibited significantly at the lower doses.
Chitosans are potent nontoxic absorption enhancers after nasal administration but their effects on the intestinal epithelium in vivo has not been studied in detail. In this study, the effects of chitosans with varying molecular weights and degrees of acetylation on the absorption of a poorly absorbed model drug (atenolol) were studied in intestinal epithelial cell layers with or without a mucus layer and in an in situ perfusion model of rat ileum. The effects of the chitosans on epithelial morphology and release of lactate dehydrogenase (LDH) into the perfusate were investigated in the in situ model. The chitosans had pronounced effects on the permeability of mucus-free Caco-2 layers and enhanced the permeation of atenolol 10- to 15-fold, with different absorption kinetics for different chitosans, in accordance with previous results. In contrast, enhancement of atenolol absorption through rat ileum was modest. LDH release from the tissues perfused with chitosans did not increase, indicating that the chitosans were used at nontoxic concentrations. Morphological examination of the perfused ileal tissues revealed more mucus discharge from the tissues exposed to chitosans than from controls, which suggested that the discharged mucus may inhibit the binding of chitosan to the epithelial surface and hence decrease the absorption-enhancing effect. This hypothesis was supported by studies with intestinal epithelial HT29-H goblet cells covered with a mucus layer. The binding of chitosan to the epithelial cell surface and subsequent absorption-enhancing effects were significantly reduced in mucus-covered HT29-H cultures. When the mucus layer was removed prior to the addition of chitosan, the cell surface binding and absorption-enhancing effects of the chitosans were increased. We conclude that the modest absorption-enhancing effects of unformulated chitosan solutions in the perfused rat ileum are a result of the mucus barrier in this tissue. This effect may be overcome by increasing the local concentrations of both chitosan and drug, i.e,. through formulation of the chitosan into a particulate dosage form.
Previously reported levels of iron absorption from common Southeast Asian meals composed of rice, vegetables, and spices were too low to be consistent with the known prevalence of iron deficiency. In the present paper the cause of the low absorption was systematically sought. Variables investigated comprised methodological errors, factors in the diet such as certain foodstuffs, or contaminants inhibiting the absorption and characteristics of the subjects accompanied by malabsorption of dietary iron. The latter was excluded by comparing the absorption from both wheat rolls and a composit rice meal in Thai and Swedish women using the absorption of a small dose of ferrous ascorbate as a common basis of comparison. Two main factors were identified as causing the low absorption in the previous studies: the homogenization of the labeled meals before serving and the use of rice flour instead of rice. Iron absorption from nonhomogenized meals of identical composition as studied previously was many times higher (on an average 0.16 mg) and was consistent with the actual prevalence of iron deficiency in lower socioeconomic groups of Thais mainly consuming the simple meals studied. Recent modifications of the method to measure nonheme iron absorption from composite meals have thus not only made the determination simpler but also more accurate.
To determine the contributions of transporter-mediated and passive absorption during an intraduodenal glucose infusion in a large animal model, six mongrel dogs had sampling catheters (portal vein, femoral artery, duodenum), infusion catheters (vena cava, duodenum) and a portal vein flow probe implanted 17 d before an experiment. Protocols consisted of a basal (-30 to 0 min) and an experimental (0-90 min) period. An intraduodenal glucose infusion of 44 micromol/(kg. min) was initiated at t = 0 min. At t = 20 and 80 min, 3-O-[3H]methylglucose and L-[14C]glucose (L-Glc) were injected intraduodenally. Phloridzin, an inhibitor of the Na+/K+ ATP-dependent transporter (SGLT1), was infused from t = 60 to 90 min in the presence of a peripheral isoglycemic clamp. Net gut glucose output was 21.1 +/- 3.0 micromol/(kg. min) from t = 0 to 60 min. Transporter-mediated glucose absorption was calculated using three approaches, which involved either direct measurements or indirect estimates of duodenal glucose analog radioactivities, to account for the assumptions and difficulties inherent to duodenal sampling. Values were essentially the same regardless of calculations used because transporter-mediated absorption was 89 +/- 1%, 90 +/- 2% and 91 +/- 2% of net gut glucose output. Phloridzin-induced inhibition of transporter-mediated absorption completely abolished passive absorption of L-Glc. We conclude that in dogs, transporter-mediated glucose absorption constitutes the vast majority of glucose absorbed from the gut and is required for passive glucose absorption. The method described here is applicable to investigation of the mechanisms of gut glucose absorption under a variety of nutritional, physiologic and pathophysiologic conditions.
The purpose of this study was to evaluate the effect of absorption enhancer on in-vivo transdermal absorption of cyclosporin using intradermal microdialysis in rats. Cyclosporin oily solutions (0.5, 2, 8% w/v) were prepared from Sandimmun (10% w/v oily oral preparation of cyclosporin) by diluting with olive oil. 1-[2-(Decylthio)ethyl] azacyclopentan-2-one (HPE-101) and glycerin were added to the cyclosporin formulation as an absorption enhancer at various concentrations between 1 and 20%. These formulations were applied to the shaved abdomen of rats treated with intradermal microdialysis at a flow rate of 2.5 microL min-1 for 6 h. Cyclosporin was immediately detected and attained a plateau in the dermal dialysate after topical application of cyclosporin oily solution alone. Cyclosporin levels in the dialysate increased with increasing cyclosporin concentrations in the formulation from 0.5 to 8% (w/v). HPE-101 did not influence cyclosporin absorption at concentrations less than 6% (w/v). Addition of 10% (w/v) HPE-101 significantly enhanced an apparent absorption rate of cyclosporin by 4.9 times. However, 20% (w/v) HPE-101 did not show the enhancing activity. On the other hand, addition of glycerin at concentrations of 6, 10, and 20% (v/v) significantly enhanced an apparent absorption rate of cyclosporin by 3.0, 6.4, and 6.9 times, respectively. The time lag for cyclosporin absorption was less than 0.21 h in all tested cases. This microdialysis study shows that glycerin is a suitable enhancer for improving the in-vivo cyclosporin absorption from the skin.
The pharmacokinetic analysis of an oral sustained-release preparation of diclofenac sodium has been investigated using multi-segment absorption models in which it has been assumed that the gastrointestinal tract can be divided into several segments in each of which the drug has its own lag-time and absorption rate constants. Plasma concentration-time data for sustained release diclofenac sodium in man were fitted both by a conventional pharmacokinetic method assuming first-order absorption and by a multi-segment absorption model. The plasma concentration of diclofenac sodium calculated on the basis of the multi-segment absorption model was found to correlate with the observed plasma concentration. It was concluded that diclofenac sodium data can be better described by a multi-segment absorption model than by a conventional pharmacokinetic model. The results also show that multi-segment absorption models are suitable for pharmacokinetic analysis of plasma drug-concentration data with irregular or multiple peaks in the absorption profiles, and also for the pharmacokinetic analysis of sustained-release preparations.
Titration techniques and K+- sensitive microelectrodes have been used to investigate the relations among HCO3(-) absorption, luminal K+, and intracellular K+ activity in in vitro Amphiuma jejunum. The HCO3(-) absorptive flux (JHCO3(-] measured by pH-stat under short circuit was reduced by removal of K+ from the medium but not by replacement of Na+ with choline. JHCO3(-) exhibited a seasonal variation when K+ was absent from the media and was increased to a maximum when K+ equaled 5 mM. Addition of K+ to a K+-free luminal medium stimulated JHCO3(-) much more than addition to the serosal medium. Acetazolamide (10(-4) M) blocked K+-stimulated HCO3(-) absorption while benzolamide reduced the short-circuit current associated with HCO3(-) absorption much more rapidly when added to the mucosal bathing medium. Intracellular K+ activity (aik) and mucosal membrane potential (psi m) of jejunal villus cells were measured with double-barreled microelectrodes. When bathed bilaterally with HCO3(-)-containing media, K+ was actively accumulated for many hours (aik = 58.5 mM) but in the presence of ouabain fell to equilibrium (16 mM) after 2 h. In contrast, when HCO3(-) absorption was induced by removal of serosal HCO3(-), aik was elevated to 83.6 mM and, after 4-h exposure to ouabain cell K+, remained far above electrochemical equilibrium at 33 mM. Tissues bathed in Na+-free (Tris) media containing ouabain retained cell K+ after 4 h at even higher levels (46 mM). Cell K+ activity was reduced by removal of K+ from either the mucosal or serosal medium. Acetazolamide reduced aik over 2 h in Na+-free media from 66 to 42 mM. The decline in aik was associated with a concomitant decline in the HCO3(-) absorptive current. It is concluded that K+ is actively accumulated across both luminal and serosal membranes of the jejunal absorptive cell and that the luminal uptake mechanism is linked to HCO3(-) absorption or an equivalent process.