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1. Intestinal absorption of glycylglycine was studied in four control subjects and six patients with tropical sprue by using a direct technique of intestinal perfusion. 2. The patients with tropical sprue showed significant impairment in the absorption of the dipeptide.
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The intestinal absorption rate constants of the five 6-fluoquinolones (norfloxacin, ciprofloxacin, pefloxacin, CNV 8802 and CNV 8804), have been estimated in the rat (n = 5) by means of an "in situ" intestinal perfusion method. Remaining 6-fluoquinol one concentrations in the perfusion liquid at fixed time (15, 30, 45, 60, 75, 90 and 120 minutes) were determined using a HPLC procedure with UV detection. Absorptions rate constants were estimated according to first order kinetics. A simple non-linear correlation between Ka and log K' on the one hand and a multiple linear correlation between Ka and the structural theoretical parameters: molar volume, dipolar moment and the charge associated to nitrogen 18 on the other, were performed. Only a correlation between Ka values as dependent variable versus dipolar moment and molecular volume values has been obtained, but this correlation is not statistically significant (p = 0.1808) and not accurate enough to have predictive value.
Bone histology and intestinal absorption of 25-hydroxyvitamin D3 (25-OHD) were investigated in 11 patients with primary biliary cirrhosis (P.B.C.). 4 patients had osteomalacia, and all these had received long-term cholestyramine. Plasma-25-hydroxyvitamin-D (25-OHD) concentrations after an oral dose of 25-OHD3 were significantly lower in the patients with P.B.C. (especially those with osteomalacia) than in normal controls. Serum calcium and urinary calcium excretion were lower, and serum-alkaline-phosphatase higher, in patients with osteomalacia. It is suggested that absorption of 25-OHD undergoing enterohepatic circulation and of dietary vitamin D is reduced in patients with P.B.C. Absorption of 25-OHD is further decreased by cholestyramine and the development of osteomalacia is thus hastened.
In order to examine the intestinal absorption of chloral hydrate (CH), free trichloroethanol (F-TCE) and trichloroacetic acid (TCA), an intestinal circulation system in dogs was developed using jejunal, ileal and colonic loops, and solutions of CH, F-TCE and TCA were circulated within them. The concentrations of these substances and their metabolites in the serum, urine, bile and circulates were then measured. In all groups, the fraction of water absorbed from the intestine was about 10% of the administered volume two hours after administration. The absorbed fraction of CH was about 50% in the jejunum and ileum, and about 40% in the colon. The absorbed fraction of F-TCE was about 60% in the jejunum, 50-60% in the ileum and about 40% in the colon, while the figures for TCA were about 40-50% in the jejunum and about 30-40% in the ileum and colon. The combined biliary and urinary excretion ratios of the administered substances and their respective metabolites to the total amounts absorbed from the intestine were about 25-30% for F-TCE, 10-15% for CH and 0.1-0.2% for TCA in all parts of the intestine two hours after administration.
This paper presents a method for the screening of natural hypoglycaemic drugs that interfere with the intestinal absorption of glucose. Luminal perfusion of the small intestine (whole length) was carried out on 24 h fasted adult Wistar rats, anaesthetized with sodium pentobarbital. Two rubber Nelaton cannulae were introduced into the organ, the first at the proximal end of the duodenum, just after the pylorus and a second larger one near the ileo-cecal valve. After a preliminary washing with warm physiological saline to remove any alimentary residues and secretions, warm saline containing glucose (plain or with added putative absorption inhibitors), was then introduced into the gut. Ten minutes later the contents was expelled with air and the preparation fully washed with plain warm saline. All perfusates were separately collected up to volume in graduated flasks kept in chipped ice. The glucose concentration was measured in triplicate samples by the specific glucose-oxidase method. The intestinal absorption of the sugar was calculated by difference from the glucose concentration found in the initial solution and in the final perfusate. The method is reliable and highly reproducible.
This study evaluates the effect of reverse electrical pacing on intestinal absorption and transit time in an enterostomy model. Twenty-five male Sprague-Dawley rats (148 to 208 gm) underwent division and anastomosis of the proximal jejunum to eliminate the proximal gastroduodenal pacemaker. A 30.0 cm loop ileostomy was formed, and leads were placed at 1.0 and 3.0 cm proximal to the stoma. Reverse pacing was done with a 0.25 Hz, 50 msec pulse at 0.1 mA. Transit time was evaluated with 1.0 ml barium gavage and was 12 +/- 4 minutes in group I controls (n = 13) versus 27 +/- 21 minutes in group II (n = 12) reverse-paced rats (p less than 0.025). D-Xylose absorption was determined in 18 rats. Levels were 14.0 +/- 3.6 mg/dl in control rats (n = 6) and 15.5 +/- 3.4 mg/dl in reverse-paced rats (n = 6). Increasing the pulse milliamperage to 2.0 mA (n = 6) increased D-xylose serum levels to 38.8 +/- 27.7 mg/dl (p less than 0.05). Transit rate and net water flux were determined in eight additional rats with 15 cm Theiry-Vella loops. Transit rate was measured with 0.2 ml of methylene blue and was 3.00 +/- 2.32 ml/min in unpaced rats compared with 9.95 +/- 0.71 ml/min with reverse pacing (p less than 0.025). Water flux studies showed that control rats had a net secretory loss of 0.20 +/- 0.48 ml/cm while paced rats absorbed 0.08 +/- 0.12 ml/cm. These data indicate that reverse electrical pacing increases transit time and nutrient and fluid absorption. These observations suggest that reverse electrical pacing may be a useful adjunct in instances of short gut associated with an enterostomy.
the intestinal absorption of total protein, IgG, albumin, beta-lactoglobulin, SCTI and trypsin was studied in newborn unsuckled piglets by feeding them either on normal colostrum or trypsin-inhibition-free colostrum. The results indicate a correlation between the molecular weights of the fed proteins and the time at which they reach their maximum concentration in the blood. Feeding of inhibition-free colostrum resulted in a significantly lower absorption. Evidently the trypsin inhibitors of sow's colostrum cause an increased efficiency in the absorption of undegraded colostrum proteins. However, as large quantities of proteins were absorbed even when inhibition-free colostrum was used for feeding, other factors must also be involved in the regulation of intestinal protein absorption.
To pharmacologically interrupt bile acid enterohepatic circulation, two compounds named BAPA-3 and BAPA-6, with a steroid structure and 1 or 2 positive charges, were obtained by conjugation of N-(3-aminopropyl)-1,3-propanediamine with one or two moieties of glycocholic acid (GC). Both BAPA-3 and BAPA-6 inhibited Na+-dependent taurocholate (TC) uptake by Xenopus laevis oocytes expressing rat Asbt, with Ki values of 28 and 16 microM, respectively. BAPA-3 reduced Vmax without affecting Km. In contrast, BAPA-6 increased Km, with no effect on Vmax. Uptake of [14C]-GC by the last 10 cm of the rat ileum, perfused in situ over 60 min, was inhibited to a similar extent by unlabeled GC, BAPA-3 and BAPA-6. However, the intestinal absorption of these compounds was lower (BAPA-6) or much lower (BAPA-3) than that of GC. When administered orally to mice, both compounds (BAPA-3>BAPA-6) reduced the bile acid pool size, which was accompanied by up-regulation of hepatic Cyp7a1 and Hmgcr and intestinal Ostalpha/Ostbeta. A tendency towards a decreased expression of hepatic Ntcp and an enhanced expression of intestinal Asbt was also observed. Serum biochemical parameters were not affected by treatment with these compounds, except for a moderate increase in serum triglyceride concentrations. In sum, our results suggest that these compounds, in particular BAPA-3, are potentially useful tools for inhibiting the intestinal absorption of bile acids in a non-competitive manner.
The present study was planned to elucidate the role of fasting on the intestinal absorption of monosaccharides particularly--glucose and xylose in inbred female albino rats. Rats (weighing 250-300 grams) were divided into three groups. One group of rats served as control while the other two were experimental. One of the experimental groups was starved for 48 hours while the other for a period of 72 hours. It was found that fasting for 72 hours causes an overall increase in absorption of glucose from small intestine. Forty-eight hours of fasting caused a significant increase in glucose absorption from distal ileum only. Increase in the glucose absorption in fasting from small intestine can well be explained on the basis of a reduction in glucose metabolism in general as an adaptation to starvation so as to leave more glucose for cerebral metabolism. No significant changes, whatsoever, were encountered with xylose absorption in fasting animals.
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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.
Gymnemic acid, a mixture of triterpene glycosides extracted from the leaves of Gymnema sylvestre, is known to inhibit the intestinal absorption of glucose in human and rats. This work examined the effect of gymnemic acid on oleic acid absorption by the method of intestinal perfusion in rats. The results showed the following. (i) Gymnemic acid potently inhibited the absorption of oleic acid in intestine. (ii) This inhibition was dose dependent and reversible. (iii) The extent of inhibition and the recovery progress were extremely similar to that of glucose absorption. (iv) Taurocholate did not affect the inhibitory effect of gymnemic acid on oleic acid absorption, but lowering its concentration facilitated the recovery from the inhibition. (v) The absorption of oleic acid was not affected by other glycosides such as phloridzin, stevioside, and glycyrrhizin. These new findings are important for understanding the roles of gymnemic acid in therapy of diabetes mellitus and obesity.
Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic used for the treatment of infections caused by methicillin-resistant staphylococci. It is water soluble, having a high molecular weight, and poorly absorbed from the gastrointestinal tract. Mixtures of VCM with Labrasol and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared to improve oral absorption of VCM. Administration of VCM solution to rat ileum at a dose of 20 mg/kg did not result in detectable plasma VCM concentration. Formulation containing 50% of Labrasol resulted in a Cmax value of 5.86+/-0.97 microg/ml and an AUC(0-6h) value of 16.06+/-1.78 microgh/ml. Addition of TPGS to VCM solution at 12.5% concentration also increased the plasma VCM concentration with a Cmax value of 4.98+/-0.45 microg/ml. But the AUC(0-6 h) (9.87+/-1.90 microgh/ml) was significantly lower than that obtained with Labrasol. The addition of 5.0 and 25.0% TPGS to solutions of VCM containing 50% of Labrasol did not result in any significant increase either in Cmax or AUC(0-6 h) of VCM. Whereas the addition of 12.5% of TPGS has resulted in an increase in Cmax and AUC(0-6 h) by 2.2 and 2.4 times, respectively, suggesting that this concentration of 50% Labrasol and 12.5% TPGS (1:0.25) was optimum for improving intestinal absorption of VCM. A dose dependent decrease in the Cmax and AUC(0-6 h) values was observed when the dose of absorption enhancers was decreased by 50% with formulation containing Labrasol and TPGS in 1:0.25 ratio. The results of the study indicate that formulations containing Labrasol and TPGS improve intestinal absorption of hydrophilic macromolecular drug, VCM.
Aflatoxin B1 (AFB1) transfer across the gastrointestinal tract was studied in rats. The rate of biliary secretion of 3H was higher when [3H]AFB1 was injected into the small intestine than when injected into the stomach. When various sites of the small intestine were perfused with the medium containing [3H]AFB1, the highest rate of disappearance of 3H from the medium was noted in the duodenum. Also the rate of biliary secretion of 3H tended to be higher when the duodenum was perfused than when the other sites were perfused. These results suggest that AFB1 is absorbed mainly from the small intestine, most efficiently from the duodenum. Uptake of AFB1 by the everted intestine in vitro was slightly greater in the jejunum than the other sites, suggesting that the cause of the differences in the intestinal absorption among various sites may reside in the transfer process of AFB1 from the epithelial cell layer to vascular circulation. Comparison of the AFB1 appearance in the mesenteric venous plasma and lymph showed that AFB1 is absorbed almost exclusively in the vein. Distribution of 3H in the mesenteric plasma on thin-layer chromatography revealed that metabolic degradation of AFB1 takes place in the duodenal and jejunal tissues during the course of AFB1 absorption. Examination of the appearance of AFB1 or 3H in the intestinal perfusate after iv injection of of AFB1 or [3H]AFB1 suggested that AFB1 and its metabolites can transfer from the blood to the intestinal lumen. The rate of the AFB1 absorption from various sites of the intestine changed with age and reproductive stage, indicating that the AFB1 transfer across the intestinal wall is under the influence of the growth and reproductive endocrine condition.
To characterize the influence of nitric oxide (NO) donors on the intestinal absorption of macromolecules, the relationship between the release rate of NO from NO donors and their absorption-enhancing effects and the effects of several scavengers and generators on the absorption-enhancing effects of NO donor were investigated. The t1/2 values of the NO release rate from 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-1-propanamine (NOC5), 3-(2-hydroxy-1-methylethyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC7) and N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine (NOC12) are 25, 5 and 100min, respectively. The absorption-enhancing effects of NO donors on the absorption of fluorescein isothiocyanate dextrans with an average molecular weight of 4400 (FD-4) are NOC5 > NOC7 > NOC12 in the colon. The lowest enhancing effect of NOC12 may be due to the slow rate of NO release. The enhancing effect of NOC7 rapidly disappeared compared with the effect of NOC5. The results raise the possibility that the difference between NOC5 and NOC7 on enhancing effect is related to the t1/2 of the NO release. The NOC7-induced enhancing effect was prevented by the co-administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide sodium salt (C-PTIO), an NO scavenger; tiron, an O2(-) scavenger; mannitol, an OH* scavenger, and deferoxamine, peroxynitrate scavenger. Pyrogallol, an O2(-) generator, potentiated the NOC7-induced enhancing effect. These results support a role for peroxynitrate, and possibly OH*, in the NO donor-induced intestinal enhancing effect.
PURPOSE: The feasibility of using proliposomes containing salmon calcitonin (sCT) and absorption enhancing agents, as an oral delivery system, to improve the intestinal absorption of sCT was explored using rats and Caco-2 cell systems. METHODS: Seventeen surfactants were examined for their effects with reference to accelerating the permeability of sCT (300 microg/ml) across Caco-2 cell monolayers, and damage to the intestinal epithelial cells, as measured by the change in transepithelial electrical resistance (TEER) across the cell monolayer. Proliposomes containing sCT (0.75%, w/w) and sodium taurodeoxycholate (NaTDC, 2.5%, w/w) (TDC proliposomes) were prepared according to the standard method using sorbitol and phosphatidylcholine as core and wall-forming materials, respectively, administered intra-duodenally to rats, and plasma concentrations of sCT were subsequently determined by LC-MS. RESULTS: Among the surfactants examined, some bile salts including NaTDC appeared to be the most advantageous when estimated based on the balance between the permeation enhancement (e.g., a 10.8-fold increase in the permeability of sCT for 0.1% NaTDC) and damage to the cells (e.g., a 3.55-fold decrease in the TEER value for 0.1% NaTDC). The administration of TDC proliposomes resulted in a 7.1-fold increase in the bioavailability (i.e., 0.49%) of sCT, when administered duodenally to rats. The size of the reconstituted liposomes in water was significantly smaller (e.g., 23.2 nm, number weighted diameter), and the entrapment efficiency (EE) of sCT in the reconstituted liposomes was 2.8-fold larger (54.9%), for TDC proliposomes, compared to proliposomes prepared without NaTDC (sCT proliposomes). CONCLUSION: A 7.1-fold increase in the bioavailability of sCT could be achieved from the TDC proliposomes. In addition to the intrinsic activity of the bile salt to fluidize the membrane, the simultaneous delivery of sCT and NaTDC to the site of absorption in the intestine via proliposomes and the subsequent formation of lipophilic ion-pair complexes between sCT and NaTDC at the site might have been contributing factors in this outstanding absorption enhancement.
OBJECTIVE: To compare the pharmacokinetics and efficacy of oral versus intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic liver disease, a known risk factor for vitamin K deficiency bleeding. DESIGN: Prospective randomised controlled study. SETTING: Paediatric Liver Unit. PATIENTS: Forty four infants less than 6 months of age with conjugated hyperbilirubinaemia. MAIN OUTCOME MEASURES: Serum concentrations of vitamin K(1) and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of vitamin K status) before and for up to four days after a single dose of mixed micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24 hours after oral K(1) with those from 14 healthy newborns given the same dose. RESULTS: At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K deficiency. Median serum K(1) concentrations were similar in the oral and intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml) of serum K(1) compared unfavourably with the much higher levels (median 77, range 11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested impaired and erratic intestinal absorption in cholestatic infants. The severity of malabsorption was such that only 4/24 (17%) achieved an incremental rise in serum K(1) > 10 ng/ml. CONCLUSIONS: The intestinal absorption of mixed micellar K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the strong association between cholestasis and late vitamin K deficiency bleeding, these data provide an explanation for the failure of some oral vitamin K(1) prophylaxis regimens in infants with latent cholestasis.