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The gastrointestinal absorption of methadone in the rat.

The absorption of dl-methadone from the gastrointestinal tract of the Sprague-Dawley rat was examined by the in vivo segment technique. Duodenal absorption, measured as a function of time and dose, followed first-order kinetics with a half-life of 15.6 min. Absorption was not influenced by prior or concomitant administration of a variety of drugs. Absorption from other regions of the intestine was similar to that from the duodenum; in contrast, absorption from the stomach was markedly slower. Gastric absorption was increased by alkalinization of stomach contents but was still considerably slower than from the duodenum. Gastric emptying of methadone appears to be the rate-limiting step in the overall gastrointestinal absorption of the drug, since the rate of emptying following intubation of the drug into the stomach was also considerably slower than the rate of duodenal absorption.

Animals↗

Relationship between volatile fatty acids and magnesium absorption in mono- and polygastric species.

In monogastric animals magnesium is absorbed from the small and large intestine. In ruminants the forestomach system, in particular the rumen, is the most important site of magnesium absorption. Various mechanisms are involved in intestinal magnesium absorption (solvent drag, diffusion, carrier-mediated transport). In the large intestine and rumen an active transepithelial magnesium transport from the mucosal to the serosal side of the epithelium was recently demonstrated. Since in the large intestine and in the rumen, volatile fatty acids (VFA, mainly acetate, propionate, butyrate) deriving from fermentation of carbohydrates represent the major anions, the influence of VFA on magnesium absorption from these parts of the gut was recently investigated. VFA at physiological concentrations stimulated magnesium absorption in both cases. In the rat large intestine VFA enhanced only magnesium absorption by the distal colon, sodium and water absorption remaining unaffected. Both in sheep rumen and in the distal colon of the rat butyrate was most effective in this regard, followed in descending order by propionate and acetate. Sodium absorption by the rat proximal colon and caecum, and by the sheep rumen, was similarly enhanced by VFA. It has been suggested that the latter effect is due to the function of VFA as intracellular proton donators for the Na+/H+ exchanger located in the apical membrane of the epithelial cells. In analogy a Mg2+/H+ exchanger, located in the apical membrane of the epithelium in the distal colon and rumen, is fully consistent with the stimulatory effects of VFA on magnesium absorption at these sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The absorption characteristics of six sustained-release theophylline preparations.

Dosing intervals for sustained-release theophylline preparations depend on the rate of formulation absorption, the rate of elimination by the patient, and clinically acceptable fluctuations in serum concentration. A comparative study of intersubject variation in fraction absorbed-time profiles, a process-independent method of comparing rates of absorption, was performed with 6 sustained-release preparations in 6 healthy male volunteers. The sulphasalazine/sulphapyridine method of assessing orocaecal transit time was implemented so that upper gastrointestinal and colonic absorption could be estimated. Time until 90% absorption varied from 4.43 hours to 7.46 hours and the mean percentages of theophylline remaining to be absorbed from the colon were limited to between 7.5% and 29.7% with the various formulations. There was a great intersubject variability in the rate of theophylline absorption and also considerable differences among the volunteers in their formulation-to-formulation absorption profiles. Promotional literature depicting mean or group data masks this variability in absorption profiles. Because host factors related to gastro-intestinal physiology impose highly variable theophylline absorption profiles on sustained-release formulations, it is technically impossible to formulate a suitable once-a-day product for the majority of patients.

Adult↗

Delayed insulin absorption due to subcutaneous edema.

A prospective study to determine if subcutaneous edema interferes with insulin absorption was performed. Forty-six patients entered the study. Three groups were formed. Twenty patients with generalized edema (Group 1), ten of them with non-insulin dependent diabetes mellitus (NIDDM). Twenty patients without edema (Group II). 10 of them with NIDDM; and six patients with mild edema (Group III). The disappearance of I125-insulin was measured throughout 360 minutes. The rate of absorption in group I was significantly lower and delayed than in group II. The amount of insulin absorbed at 360 minutes was 3 to 4 fold lower in group I than in group II (p 0.001). Group III had intermediate values. The peak of plasma I125-insulin level was 3 to 4 fold lower in group I than group II. The impairment of insulin absorption in subjects with edema was more evident in those with NIDDM. In conclusion, this study demonstrates that subcutaneous edema impairs insulin absorption. Insulin absorption from subcutaneous tissue varies due to several conditions, resulting in a difficult glycemic control. Previous studies have shown that insulin absorption is affected by several factors as the site of injection, room and skin temperature, physical exercise, the thickness of adipose tissue, local massage, and local degradation of insulin. Edema due to chronic complications such as nephropathy and cardiopathy often occurs in long-standing diabetic subjects. However, the effects of edema of the skin and subcutaneous tissue on insulin absorption has not been previously examined. The aim of this study was to assess if edema affects the absorption of insulin.

Abdomen↗

Mechanisms of action of plant sterols on inhibition of cholesterol absorption. Comparison of sitosterol and sitostanol.

The effects of two different plant sterols on intestinal cholesterol absorption were compared in normal volunteers by an intestinal perfusion study during a control period followed by high dose infusion of sitosterol or sitostanol (3.6 mumol/min), to which subjects were allocated in a randomized manner. Cholesterol absorption during the control period was similar in the two groups, averaging 0.88 +/- 0.48 mumol/min (32 +/- 11%) for group I (sitosterol) and 0.68 +/- 0.33 mumol/min (29 +/- 9%) for group II (sitostanol). The infusion of a high dose of sitosterol resulted in a significant reduction of cholesterol absorption to 0.47 mumol/min (16%). Following the same dose of sitostanol, cholesterol absorption diminished significantly to 0.15 +/- 0.11 mumol/min (5.1 +/- 2.9%). Overall cholesterol absorption declined during sitosterol infusion by almost 50%, whereas sitostanol infusion caused a reduction of cholesterol absorption by almost 85%. These findings of a more effective inhibition of cholesterol absorption by sitostanol might confirm the observation recorded by others that an increase in hydrophobicity of a plant sterol results in a higher affinity but lower capacity to mixed micells. This may cause an effective displacement of cholesterol from micellar binding and therefore diminished cholesterol absorption.

Cholesterol↗

Decreased colostral immunoglobulin absorption in calves with postnatal respiratory acidosis.

The effect of postnatal acid-base status on the absorption of colostral immunoglobulins by calves was examined in 2 field studies. In study 1, blood pH at 2 and 4 hours after birth was related to serum IgG1 concentration 12 hours after colostrum feeding (P less than 0.05). Decreased IgG1 absorption from colostrum was associated with respiratory, rather than metabolic, acidosis, because blood PCO2 at 2 and 4 hours after birth was negatively related to IgG1 absorption (P less than 0.05), whereas serum bicarbonate concentration was not significantly related to IgG1 absorption. Acidosis was frequently observed in the 30 calves of study 1. At birth, all calves had venous PCO2 value greater than or equal to 60 mm of Hg, 20 of the calves had blood pH less than 7.20, and 8 of the calves had blood bicarbonate concentration less than 24 mEq/L. Blood pH values were considerably improved by 4 hours after birth; only 7 calves had blood pH values less than 7.20. Calves lacking risk factors for acidosis were examined in study 2, and blood pH values at 4 hours after birth ranged from 7.25 to 7.39. Blood pH was unrelated to IgG1 absorption in the calves of study 2. However, blood PCO2 was again found to be negatively related to colostral IgG1 absorption (P less than 0.005). Results indicate that postnatal respiratory acidosis in calves can adversely affect colostral immunoglobulin absorption, despite adequate colostrum intake early in the absorptive period.

Absorption↗

Rectal absorption enhancement of gentamicin in rabbits from hollow type suppositories by sodium salicylate or sodium caprylate.

The absorption of gentamicin (GM) from the rectum of rabbits after coadministration of GM (60 mg) and sodium salicylate (SA) or sodium caprylate (CA) as absorption-enhancing agents was investigated. Two types of hollow type suppositories were used--a conventional type (Type I) and a release-restricted type (Type II). Without SA or CA, GM was not absorbed. However, GM absorption was marked when 90 mg of solid SA or CA was added (the bioavailability of GM was 58% with SA, and 59% with CA). The enhancing effect of SA or CA (30 mg) in solid or aqueous solution form on GM absorption was evaluated using the Type I suppository. In the case of SA, the highest plasma GM level (Cmax 15.3 +/- 1.7 micrograms/ml, AUC0-4 27.3 +/- 3.9 h.micrograms/ml) was obtained following coadministration of powdered GM and SA; the plasma GM level (Cmax 1.5 +/- 0.6 micrograms/ml, AUC0-4 3.0 +/- 1.3 h.micrograms/ml) following the administration of a solution of GM and SA was significantly decreased as compared with the results using the powdered form. In the case of CA, the plasma GM level (Cmax 14.8 +/- 4.5 micrograms/ml, AUC0-4 25.4 +/- 8.7 h.micrograms/ml) following administration of the solution form was not significantly decreased in comparison with the results obtained using the powdered form. A marked increase in the enhancing effect of SA on the rectal GM absorption was found following use of Type II suppositories when GM and SA were coadministered in solution form. However, the GM absorption after coadministration of GM and CA using Type II suppositories was not significantly different from the absorption resulting from use of Type I suppositories. Our results suggest that the form and concentration of drug should not be ignored in evaluating the enhancing effects of SA or CA on the rectal absorption of poorly absorbed drugs such as GM.

Administration, Rectal↗

Effect of absorbable and nonabsorbable sugars on intestinal calcium absorption in humans.

The effects of glucose, galactose, and lactitol on intestinal calcium absorption and gastric emptying were studied in 9, 8, and 20 healthy subjects, respectively. Calcium absorption was measured by using a double-isotope technique and the kinetic parameters were obtained by a deconvolution method. The gastric emptying rate was determined with 99mTc-diethylenetriaminepentaacetic acid and was expressed as the half-time of the emptying curve. Each subject was studied under two conditions: (a) with calcium alone and (b) with calcium plus sugar. Glucose and galactose increased the calcium mean transit time and improved the total fractional calcium absorption by 30% (p less than 0.02). Lactitol decreased the mean rate of absorption (p less than 0.001) and reduced the total fractional calcium absorption by 15% (p less than 0.001). The gastric emptying rate did not appear to influence directly the kinetic parameters of calcium absorption. These results show that both glucose and galactose exert the same stimulatory effect as lactose on calcium absorption in subjects with normal lactase whereas lactitol mimics the effects of lactose in lactase-deficient patients. Thus the absorbability of sugars determines their effect on calcium absorption.

Adult↗

Absorption of theophylline from a sustained-release theophylline tablet formulation, Theo-Dur.

The absorption kinetics of theophylline after single oral administration of a sustained-release theophylline tablet formulation, Theo-Dur, were studied in healthy volunteers. The pharmacokinetic parameters were estimated by utilizing a one-compartment model with zero-order or first-order absorption according to the procedure "Praxis". The release of theophylline from the formulation in the in vitro dissolution study was shown to be an apparent zero-order process. The in vivo studies demonstrated that the time required to reach maximum plasma concentration of theophylline was about 8 h. The mean residence time in vivo, MRT, was 18.6 h. The present study also showed that the formulation was good sustained-release properties with adequate bioavailability and that the in vitro sustained-release characteristic was confirmed to be reflected in the plasma concentration-time profile of theophylline in the in vivo. The computer-predicted concentrations of theophylline based on the zero-order absorption model fitted to the observed data points better than those based on the first-order absorption model. The regression curves obtained by nonlinear least squares method based on the first-order absorption model underestimate the maximum observed plasma concentrations of theophylline. There was a highly significant relationship between observed and calculated around the maximum plasma concentration data based on the zero-order absorption model. These results show that the drug absorption from the formulation is best described by an apparent zero-order rather than a first-order absorption model.

Absorption↗

A dual, concentration-dependent absorption mechanism of linoleic acid by rat jejunum in vitro.

Linoleic acid absorption was studied using everted rat jejunal sacs. At low concentrations (42-1260 microM), the relationship between linoleic acid concentration and its absorption rate fitted best to a rectangular hyperbola. At high concentrations (2.5-4.2 mM) the relationship between the two parameters was linear. The separate additions of 2,4-dinitrophenol, cyanide, or azide, or decrease in the incubation temperature from 37 to 20 degrees C did not change the absorption rate of linoleic acid. Absorption rate of linoleic acid at low concentrations increased as the hydrogen ion and taurocholate concentrations were increased or as the unstirred water layer thickness was decreased. Linoleic acid absorption rate was decreased after the additions of lecithin, oleic, linolenic, and arachidonic acids or the substitution of taurocholate with the nonionic surfactant Pluronic F 68. These observations indicate that a concentration-dependent, dual mechanism of transport is operative in linoleic acid absorption. Facilitated diffusion is the predominant mechanism of absorption at low concentrations, while at high concentrations, simple diffusion is predominant. At low concentrations, the absorption rate of linoleic acid is influenced by the pH, surfactant type and concentration, the simultaneous presence of other polyunsaturated fatty acids, and the thickness of the unstirred water layer.

Animals↗

Gastrointestinal absorption of neptunium in primates: effect of ingested mass, diet, and fasting.

Absorption and retention of neptunium were determined in baboons after intragastric administration of neptunium nitrate solutions at pH 1. The effects of mass, diet, and fasting on absorption were studied. At higher mass levels (400-800 micrograms Np/kg), absorption was about 1%; at lower mass intakes (0.0009-0.005 micrograms Np/kg), absorption was reduced by 10- to 20-fold. The addition of an oxidizing agent (Fe3+) increased gastrointestinal absorption and supported the hypothesis of a reduction of Np (V) when loss masses were ingested. Diets depleted of or enriched with hydroxy acids did not modify retention of neptunium but increased urinary excretion with increasing hydroxy acid content. The diet enriched with milk components reduced absorption by a factor of 5. Potatoes increased absorption and retention by a factor 5, not necessarily due to the effect of phytate. Fasting for 12 or 24 h increased retention and absorption by factors of about 3 and 10, respectively. Data obtained in baboons when low masses of neptunium were administered suggest that the f1 factor used by ICRP should be decreased. However, fasting as encountered in certain nutritional habits is a factor to be taken into consideration.

Animals↗

Effects of duration of fast and animal age on the gastrointestinal absorption of plutonium.

The fraction of plutonium absorbed after oral administration of Pu(VI) to 24-h-fasted mice was 19 X 10(-4), 13-fold higher than in fed mice, 1.4 X 10(-4). We have investigated the relevance of the high gastrointestinal (GI) absorption value for the 24-h-fasted animals in setting drinking water standards for humans. When fasting was initiated at the beginning of the active phase of the mouse's daily activity cycle (when they would normally eat), plutonium GI absorption rose from 2.8 X 10(-4) at zero-time to a level typical of the 24-h-fasted mouse after only 2 h of fasting. In contrast, in mice allowed to eat for 4 h into their active phase prior to initiation of the fast (meal-fed mice), 8 h of fasting were required before GI absorption rose to a level similar to that of the 24-h-fasted mouse. The fraction of plutonium retained after gavage administration of Pu(VI) to 1-day-old rats was 74 X 10(-4), 70-fold higher than the value for fed adults. Retention after GI absorption in neonates remained 30- to 70-fold higher than in adults until weaning. One week after weaning, the fraction absorbed and retained by fed weanling rats was the same as that for fed adults, 1 X 10(-4). Drinking water standards for plutonium have been set based on GI absorption values for fed adult animals. The 10- to 100-fold increases in plutonium absorption in young and fasted animals reported by ourselves and others, and the rapid rise to fasted levels of absorption at the start of the animal's active phase, indicate that consideration should be given to elevated levels of plutonium absorption in young and fasted individuals.

Aging↗

Absorption of 7-ketolithocholic acid in rat jejunum, ileum and colon.

7-Ketolithocholic acid is a bile acid which is formed in the intestine of man by bacterial oxidation of chenodeoxycholic acid and ursodeoxycholic acid. In contrast to deoxycholic acid and lithocholic acid 7-ketolithocholic acid after its intestinal absorption may be reduced in the liver to chenodeoxycholic acid or ursodeoxycholic acid. In the present study absorption of 7-ketolithocholic acid in jejunum, ileum, and colon was measured. When 7-ketolithocholic acid was perfused with a concentration of 0.025 mmol/l the absorption in the jejunum was 6.2 +/- 0.9 nmol/cmxh (mean +/- SD), in the ileum 8.1 +/- 0.2 nmol/cmxh, and in the colon 11.2 +/- 1.7 nmol/cmxh. The absorption of 7-ketolithocholic acid in jejunum, ileum, and colon was equal to the absorption of ursodeoxycholic and chenodeoxycholic acid. The equal absorption rates of 7-ketolithocholic, ursodeoxycholic, and chenodeoxycholic acid indicate, that substitution of the 7-hydroxyl group by the 7-keto group has no influence on the intestinal absorption of bile acids. The excellent colonic absorption of 7-ketolithocholic acid demonstrates, that not only the small intestine but also the colon contributes to the enterohepatic circulation of bile acids.

Animals↗

Blood flow an intestinal absorption.

Intestinal blood flow interacts with intestinal absorption at several levels and affects absorption through several mechanisms. The precise relationships are difficult to define because, at present, there is not an adequate technique available for measuring blood flow to the absorptive site. The absorption of certain nutrients requires O2 delivered through the blood for maintenance of carrier-mediated transcellular transport. Both altered capillary pressure, which may or may not accompany altered blood flow because of myogenic autoregulation, and changes in absorption can influence tissue hydrostatic and colloid osmotic pressure and also epithelial and interstitial space conductance. These latter, in turn, can change the rate of passive ultrafiltration for a constant driving force. Changes in blood flow can also influence the rate of washout of absorbed substances. Countercurrent exchange in the villous vasculature can buffer the rate of absorption of some substances and may also facilitate the absorption of water. Regulatory agents such as hormones or neurotransmitters can affect blood flow and absorption both independently and interactively. Agents that cause active intestinal secretion may have their effects modified by consequent changes in blood flow.

Animals↗

Factors affecting the absorption and excretion of lead in the rat.

A reliable method for studying lead absorption and excretion in rats is described. Lead absorption occurs primarily in theduodenum where lead enters the epithelial mucosal cells. There is a relative mucosal block for lead with increasing intraluminal doses. Certain substances which bind lead and increase its solubility enhance its absorption. Iron, zinc, and calcium decrease the absorption of lead without affecting its solubility, probably by competing for shared absorptive receptors in the intestinal mucosa. The total body burden of lead does not affect lead absorption. Thus, lead does not have a feedback mechanism which limits absorption. Lead absorption is increased during rapid periods of growth and in iron-deficient animals. It is diminished with starvation and in iron-overloaded animals. The excretion and kinetics of tracer doses of radiolead were quantified. Erythrocytes seem to serve an important role in transport. Excretion occurs in urine and stool. Bile is an important route of excretion in the gut. Although most of a tracer dose is rapidly excreted, the excretory process is limited permitting lead accumulation primarily in bone.

Anemia, Hypochromic↗

Net absorption of 3-methylindole and indole in cattle after oral administration of L-tryptophan.

The time course and quantity of 3-methylindole (3MI) and indole absorbed after oral administration of L-tryptophan (TRP) was determined in 2 steers. The relationship between the appearance of 3MI and indole in the rumen and blood plasma to absorption of 3MI and indole was also studied. Two Hereford X Angus steers with portal vein, mesenteric vein, and femoral (steer 1) or iliac (steer 2) artery catheters were used. Absorption rates from the portal drained viscera (net absorption) of 3MI and indole were determined by the product of portal and arterial concentration difference and blood flow. Blood flow was determined by primed continuous infusion of p-aminohippuric acid into a mesenteric vein. Three absorption measurements 30 minutes apart were taken at midpoint times of 0, 12, 24, 36, and 48 hours after oral administration of 0.4 g of TRP/kg of body weight. Steer 1 was dosed twice resulting in a total of 45 absorption measurements. Net absorption of 3MI and indole peaked at an average of 1.05 and 0.81 g/hr, respectively. By 48 hours, 29.2% and 15.3% of the TRP dose were accounted for by 3MI and indole absorption, respectively. Closed system in vitro incubations of TRP with ruminal fluid from the same 2 steers resulted in a TRP to 3MI conversion of 23.2% and a TRP to indole conversion of 10.7%. Net absorption of 3MI and indole closely followed and was correlated with concentration of 3MI and indole in ruminal fluid and blood plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

Effect of meal composition on calcium absorption: enhancing effect of carbohydrate polymers.

Meal components including fat, fiber, and carbohydrates can influence the intestinal absorption of calcium; such interactions may be of even greater importance in the presence of intestinal disease. This study compares intestinal absorption of 47CaCl2 administered in four ways: in water, within a standard meal, with a liquid formula (Ensure, Ross Laboratories, Columbus, Ohio), or with a glucose polymer solution (Frodex-15, Ross). Studies were carried out in 9 patients with ileal resection, 3 patients with jejunoileal bypass, and 14 controls. Fractional calcium absorption from water was lower in patients than in controls. Absorption was enhanced 1.5- to 5-fold when 47CaCl2 was administered with a liquid formula diet containing a glucose polymer or with the glucose polymer alone. Patients with the lowest calcium absorption from breakfast showed the greatest effect of calcium ingestion with formula or glucose polymer. These findings further emphasize the importance of meal composition on calcium absorption and provide a possible mechanism for enhancing calcium absorption in some patients with chronically impaired absorption.

Adult↗

Cholesterol absorption in baboons.

We estimated the effects of age, sex, saturated and polyunsaturated dietary fat, and two levels of dietary cholesterol intake on cholesterol absorption in juvenile baboons between 15 and 51 months of age. We compared the reproducibility of methods of measuring cholesterol absorption within animals, and also compared estimates of percentage cholesterol absorption by three different methods. Cholesterol absorption was significantly greater in all diet groups at 27 and 39 months of age than it was at 15 or 51 months (P < 0.001). Cholesterol absorption (%) was significantly greater in animals fed low cholesterol diets than it was in animals fed high cholesterol diets. However, cholesterol absorption was not affected by type of fat (saturated or unsaturated) in the diet or by sex. The range of reproducibility (within-animal standard deviation) of percentage cholesterol absorption for different diet groups was 3.35 to 3.90% for the Borgström method (1969. J. Lipid Res. 10: 331--337), 4.67 to 7.30% for the Sodhi method (1971. Proc. Soc. Exp. Biol. Med. 137: 277-279), and 3.69 to 7.15% by a combined isotopic chromatographic method (Method I). Percentage absorption measured by either the Sodhi method or Method I was significantly greater than that measured by the Borgström method.

Aging↗