Simple test of intestinal calcium absorption measured by stable strontium.

A clinical test of intestinal calcium absorption has been developed using non-radioactive stable strontium as a calcium tracer. In nine elderly subjects there was a close correlation between the fractional absorption of strontium and radioactive calcium (45Ca) during a five hour period after the simultaneous oral administration of the two tracers. Comparable precision was achieved with each tracer in six subjects in whom the test was repeated after two weeks. The effect of food on strontium absorption was examined in a further 33 normal subjects (age 21-60 years), and the administration of the strontium with a standard breakfast was shown to reduce the variance at individual time points. A simplified test in which serum strontium concentration was measured four hours after the oral dose given with a standard breakfast was adopted as the routine procedure. The normal range (mean (2 SD], established over 97 tests in 53 patients, was 7.0-18.0% of the dose in the extracellular fluid. A further 30 patients with possible disorders of calcium absorption (10 with primary hyperparathyroidism and 20 with coeliac disease) were studied by this standard test. In both groups of patients the mean four hour strontium values were significantly different from normal. This standard strontium absorption test allows assessment of calcium absorption with sufficient sensitivity and precision to have a wide application in clinical practice.     

Cholesterol absorption and turnover in rhesus monkeys as measured by two methods

We compared the absorption of cholesterol in seven rhesus monkeys (four high-responders and three low-responders) as measured by two methods: 1) the dual isotope plasma ratio method of Zilversmit (1972. Proc. Soc. Exp. Biol. Med. 140: 862) and 2) the single isotopic meal feeding technique of Borgstr?m (1969. J. Lipid Res. 10: 331). We also compared the cholesterol pool sizes calculated by kinetic analysis of the plasma cholesterol specific activity decay curves obtained after simultaneous administration of [(3)H]- and [(14)C]cholesterol, one given intravenously and the other orally. The ratio of orally to intravenously administered cholesterol radioactivity in plasma did not attain constancy until 6 weeks after isotope administration. Therefore, the percent absorption of cholesterol was calculated by the Zilversmit method 8 weeks after the administration of isotopes. The mean percent absorption of cholesterol by the Borgstr?m method was 66.3 +/- 5.1 (S.E.) and by the Zilversmit method was 70.3 +/- 7.4. The differences were not statistically significant. However, in two of seven monkeys the percent absorption of cholesterol calculated by the Zilversmit method was higher by 10.4 and 22.6 percentage points than the values obtained by the Borgstr?m method. Cholesterol absorption by either method was higher in the high-responding monkeys than in the low-responding group. The sizes of the rapidly exchangeable pool or the minimum estimate of the total body pool of cholesterol were similar for all monkeys or for either the low-responding or the high-responding animals and were also similar when calculated using the data from either the orally or the intravenously administered radioactive cholesterol. Cholesterol synthesis was significantly higher in the low-responding monkeys (115 mg/day) than in the high-responding (64 mg/day). The present study and our previous studies support the hypothesis that a major factor causing the difference in response of plasma cholesterol to dietary cholesterol between the high- and low-responding rhesus monkeys is a difference in the intestinal absorption of cholesterol.-Bhattacharyya, A. K., and D. A. Eggen. Cholesterol absorption and turnover in rhesus monkeys as measured by two methods.     

Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-d3) dilution in rats

There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3)-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.     

Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats

This study investigated the pharmacokinetic properties of crocin following oral administration in rats. After a single oral dose, crocin was undetected while crocetin, a metabolite of crocin, was found in plasma at low concentrations. Simultaneously, crocin was largely present in feces and intestinal contents within 24h. After repeated oral doses for 6 days, crocin remained undetected in plasma and plasma crocetin concentrations were comparable to the corresponding data obtained after the single oral dose. Furthermore, the absorption characteristics of crocin were evaluated in situ using an intestinal recirculation perfusion method. During recirculation, crocin was undetected and low concentrations of crocetin were detected in plasma. The concentrations of crocin in the perfusate were reduced through different intestinal segments, and the quantities of drug lost were greater throughout the colon. These results indicate that (1) orally administered crocin is not absorbed either after a single dose or repeated doses, (2) crocin is excreted largely through the intestinal tract following oral administration, (3) plasma crocetin concentrations do not tend to accumulate with repeated oral doses of crocin, and (4) the intestinal tract serves as an important site for crocin hydrolysis.     

Calculation of stable isotope enrichment tracer kinetic procedures

The choice of method of expressing isotopic enrichment in tracer kinetic experiments utilizing stable isotopes was found to affect the calculation of tracee pool size and half-life. The most commonly used definition, the difference between enriched and natural abundance, i.e. atom percent excess, was found to result in significant error in model systems when the dose of tracer was 10% of the pool size. Errors in determining first-order rate constants of efflux and in pool sizes decreased with decreasing ratio of tracer to tracee. Error in determining pool size increased with longer 'sampling' periods, while error in determining the rate constant increased with shorter sampling periods. Of three less frequently used expressions of isotopic enrichment two were found to yield the exact answers in model systems. The correct expressions of isotopic enrichment were linear functions of the quantity of tracer in the system. A practical example demonstrated the effect of choice of expression of enrichment on estimates of whole body copper pool size and turnover in dairy cattle.     

Cholesterol absorption efficiency declines at moderate dietary doses in normal human subjects.

While unphysiologically large cholesterol doses are known to reduce percent cholesterol absorption, smaller amounts are reported to have no effect in human subjects. To determine the dose;-response relation between dietary cholesterol consumed and the efficiency of intestinal cholesterol absorption, we fed 18 normal subjects two test meals containing different amounts of natural cholesterol. In each test pentadeuterated cholesterol tracer was given orally, hexadeuterated cholesterol tracer was given intravenously, and the tracer ratio was measured in plasma 4 days later by gas chromatography/negative ion mass spectrometry. Baseline cholesterol absorption in the presence of 26 mg cholesterol tracer was 40.7 +/- 2.3%. This decreased by 4.9 percentage points (P = 0.05) when a total of 188 mg cholesterol was included in the meal and by 15.6 percentage points (P = 0.006) when 421 mg cholesterol was given, showing that the efficiency of cholesterol absorption declines appreciably even with modest increases in cholesterol dose. Considerable variation was noted in the response of different subjects and, on the higher cholesterol dose, dietary cholesterol absorption varied 5-fold from 40 mg to 212 mg. Fasting plasma insulin was correlated with the ability to absorb higher cholesterol doses without loss of efficiency (r(s) = 0.700, P = 0.036). Percent cholesterol absorption in a single meal is significantly influenced by the amount of cholesterol in that meal, suggesting that acute dietary factors influencing cholesterol absorption need further study.     

Validation of a dual-isotope plasma ratio method for measurement of cholesterol absorption in rats

Several methods for measuring cholesterol absorption in the rat have been compared. After administration of an oral dose of labeled cholesterol ((14)C or (3)H) and an intravenous dose of colloidal labeled cholesterol ((3)H or (14)C) the ratio of the two labels in plasma or whole blood 48 hr or more after dosing compared closely to the ratio of areas under the respective specific activity-time curves. The area ratio method is independent of a time lag between the appearance of oral and intravenous label in the bloodstream. Both measures of cholesterol absorption agree fairly well with a method based on measuring the unabsorbed dietary cholesterol in a pooled fecal sample. The plasma isotope ratio method gave more reproducible results than the fecal collection method when the measurement was repeated in the same animals 5 days after the first measurement. Cholesterol absorption was overestimated by the use of Tween 20-solubilized labeled cholesterol for the intravenous dose. The plasma disappearance curves of injected labeled colloidal cholesterol and cholesterol-labeled chylomicrons infused intravenously over a 3.5-hr period in the same animal coincided within experimental error from the first day until 75 days after injection. The plasma isotope ratio method for cholesterol absorption gave the same results in rats practicing coprophagy as in those in which this practice was prevented. The addition of sulfaguanidine to the diet lowered cholesterol absorption as measured by the plasma isotope ratio to the same degree as that measured by the fecal collection method.     

Comparison of effects of verapamil, low calcium diet and betamethasone on duodenal calcium absorption efficiency in the chick

The results indicate that oral administration of verapamil for 2 weeks to the chick is followed by an increase in the efficiency of the duodenal absorption of calcium. In these chicks both a decrease in serum calcium level and an increase in the activity of renal 1 alpha-hydroxylase were observed. The increased calcium absorption following prolonged treatment with verapamil resembles that induced by a low calcium diet. The mechanism of both responses presumably involves an increased production of 1,25-dihydroxyvitamin D3. Both verapamil- and low calcium diet-induced adaptations are capable of overcoming the inhibitory action of betamethasone on intestinal calcium absorption. No effects on calcium absorption were noted if verapamil was administered intraperitoneally which suggests that verapamil exerts its action directly on the intestinal mucosa.     

Oral absorption and excretion of icaritin, an aglycone and also active metabolite of prenylflavonoids from the Chinese medicine Herba Epimedii in rats

Icaritin (ICT) is a main aglycone and also active intestinal metabolite of prenylflavonoids from the Chinese medicine Herba Epimedii. In the present study, the oral absorption and excretion of this compound was investigated using rats for exploring its fate in the body, so as to better understanding its in vivo pharmacological activities. The free (parent) and total (parent plus conjugated metabolites) ICT concentrations in rat plasma, urine and bile, after intravenous (i.v.) and oral administration both at 5mg/kg, were determined before and after enzymatic hydrolysis with β-glucuronidase/sulphatase, respectively, by a HPLC-UV method. The results showed that free ICT plasma concentration after i.v. dose was rapidly decreased with average t(1/2, λ) of 0.43h, while the total ICT concentration was decreased slowly with t(1/2, λ) of 6.86h. The area under the curve of ICT conjugated metabolites was about 11-fold higher than that of free ICT. The majority of ICT in the body was excreted from the bile with 68.05% of dose over 8h after i.v. dosing, in which only 0.15% was in parent form. While very little amount of ICT was excreted from the urine with 3.01% of dose over 24h, in which the parent form was 0.62%. After oral administration, very little amount of parent ICT was detected only in 0.5, 1 or 2h plasma samples with the concentration less than LOQ, however, its total plasma concentration after enzymatic hydrolysis treatment was at relative high level with average maximum concentration of 0.49μg/ml achieved at 1h post dose. The oral bioavailability of ICT was 35% of dose, estimated by its total plasma drug concentrations. It is concluded that ICT can be easily absorbed into the body, and then rapidly conversed to its conjugated metabolites, and finally removed from the body mainly by biliary excretion.     

Double isotope tracer method for measuring fractional zinc absorption: theoretical analysis

Several approaches for estimation of fractional zinc absorption (FZA) by calculating the ratio of oral to intravenous stable isotopic tracer concentrations (at an appropriate time) in urine or plasma after their simultaneous administration have been proposed in the last decade. These simple-to-implement approaches, often referred to as the double isotopic tracer ratio (DITR) method, are more attractive than the classical "deconvolution" method and the more commonly used single-tracer methods based on fecal monitoring and indicator dilution, after oral or intravenous tracer administration, respectively. However, the domain of validity of DITR for measuring FZA has recently been questioned. In this paper, we provide a theoretical justification of the validity of four different "approximate" formulations of the DITR technique by demonstrating mathematically that their accuracy is a consequence of the particular properties of zinc kinetics.     

Determination of deoxycholic acid pool size and input rate using [24-13C]deoxycholic acid and serum sampling

We have developed an isotope dilution method for determination of deoxycholic acid pool size and input rate which employs oral administration of 50 mg of [24-13C]deoxycholic acid and serum sampling. The method has been validated by classical isotope dilution technique using [24-14C]deoxycholic acid and bile sampling in five patients with colonic adenomas. Excellent agreement between pool sizes and input rates determined with 13C/12C isotope ratio measurements in serum and 14C measurements in bile was obtained when isotope ratios were measured in the conjugated fraction of deoxycholic acid in serum. We conclude that pool size and input rate of deoxycholic acid can accurately be determined by blood sampling after oral administration of [24-13C]deoxycholic acid, therewith eliminating the use of radioactive tracers and the need for bile sampling.     

Stable isotopes of minerals as metabolic tracers in human nutrition research

Enriched stable isotopes used as tracers have proven to be valuable in studies of the absorption and metabolism of minerals. Unlike radioisotopes, they can be used in high-risk population groups such as infants, children, and pregnant or lactating women. Estimates of mineral absorption can be made from the oral administration of a single tracer or from two tracers, one given orally and the other intravenously (IV). It is possible to determine the metabolism of the mineral with modeling based on the amount of the tracer or tracers in different biological samples. One of the key decisions in studies of this type is determining which enriched isotope and what amount to use. An example is given of calculations to estimate and compare the amounts of tracers needed for an absorption study. Methods for calculating the amounts of tracer in oral and IV doses are presented, and limits of detection and quantitation are discussed in terms of percent of enrichment and related to isotope ratio measurement precision. A general review of the use of mass spectrometric instruments for quantifying various stable isotopes is given.     

Human biokinetics of strontium. Part I: Intestinal absorption rate and its impact on the dose coefficient of 90Sr after ingestion

Intestinal absorption of strontium (Sr) in thirteen healthy adult German volunteers has been investigated by simultaneous oral and intravenous administration of two stable tracer isotopes, i.e. (84)Sr and (86)Sr. The measured Sr tracer concentration in plasma was analyzed using the convolution integral technique to obtain the intestinal absorption rate. The results showed that the Sr labeled in different foodstuffs was absorbed into the body fluids in a large range of difference. The maximum Sr absorption rates were observed within 60-120 min after administration. The rate of absorption is used to evaluate the intestinal absorption fraction, i.e. the f (1) value for various foodstuffs. The equivalent and effective dose coefficients for ingestion of (90)Sr were calculated using these f (1) values, and they were compared with those recommended by the International Commission on Radiological Protection (ICRP). The geometric and arithmetic means of the f (1) values are 0.38 and 0.45 associated with a geometric standard deviation and a standard deviation of 1.88 and 0.22, respectively. The 90% confidence interval of the f (1) values obtained in the present study ranges from 0.13 to 0.98. Expressed as the ratio of the 95 and 50% percentiles of the estimated probability, the uncertainty for the f (1) value corresponds to a factor of 2.58. The effective dose coefficients of (90)Sr after ingestion are 6.1 x 10(-9) Sv Bq(-1) for an f(1) value of 0.05, 1.0 x 10(-8) Sv Bq(-1) for 0.1, 1.9 x 10(-8) Sv Bq(-1) for 0.2, 2.8 x 10(-8) Sv Bq(-1) for 0.3, 3.6 x 10(-8) Sv Bq(-1) for 0.4, 5.3 x 10(-8) Sv Bq(-1) for 0.6, 7.1 x 10(-8) Sv Bq(-1) for 0.8, and 7.9 x 10(-8) Sv Bq(-1) for 0.9, respectively. Taking the effective dose coefficient of 2.8 x 10(-8) Sv Bq(-1) for an f (1) value of 0.3, which is recommended by the ICRP, as a reference, the effective dose coefficient of (90)Sr after ingestion varies by a factor of 2.8 when the f (1) value changes by a factor of 3, i.e. it decreases from 0.3 to 0.1 or increases from 0.3 to 0.9, respectively.     

Ion microscopic imaging of calcium during 1,25-dihydroxyvitamin D-mediated intestinal absorption

A combination of ion microscopic and conventional radionuclide techniques was employed to investigate the temporal-spatial dynamics of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]-stimulated intestinal calcium (Ca) absorption. At varying times following the administration of a single intravenous dose of 1,25(OH)₂D₃, to vitamin D-deficient chicks, transepithelial transport and tissue retention of Ca were quantitated in vivo, using the ligated duodenal loop technique and⁴⁷Ca as the tracer. The localization of Ca in the intestinal tissue during absorption was monitored by ion microscopy, using the stable Ca isotope,⁴⁴Ca, as the absorbed species. There was little transepithelial absorption of Ca in the vitamin D-deficient animals despite a substantial tissue accumulation of luminally derived Ca, the latter localizing predominantly in the brush border region of the enterocyte, as shown by the⁴⁴Ca-ion microscopic images. The early (30 min-1 h) response to 1,25(OH)₂D₃ was an increased tissue uptake of luminal⁴⁷Ca, which also primarily associated with the brush border region, again as shown by ion microscopy. At 2–4 h after the 1,25(OH)₂)D₃ dose, there was a progressive redistribution of Ca from the brush border region throughout the cytoplasm and into the lamina propria. At 8–16 h,⁴⁷Ca absorption was maximal and⁴⁴Ca was sparsely distributed in the intestinal tissue.⁴⁷Ca absorption gradually declined and reached pre-dose levels by 72 h. At this time, tissue⁴⁴Ca was again largely limited to the brush border region. These results provide support for the multiple actions of 1,25(OH)₂D₃ on the intestinal Ca absorption     

Effects of a single dose of menadione on the intestinal calcium absorption and associated variables

The effect of a single large dose of menadione on intestinal calcium absorption and associated variables was investigated in chicks fed a normal diet. The data show that 2.5 micro mol of menadione/kg of b.w. causes inhibition of calcium transfer from lumen-to-blood within 30 min. This effect seems to be related to oxidative stress provoked by menadione as judged by glutathione depletion and an increment in the total carbonyl group content produced at the same time. Two enzymes presumably involved in calcium transcellular movement, such as alkaline phosphatase, located in the brush border membrane, and Ca(2+)- pump ATPase, which sits in the basolateral membrane, were also inhibited. The enzyme inhibition could be due to alterations caused by the appearance of free hydroxyl groups, which are triggered by glutathione depletion. Addition of glutathione monoester to the duodenal loop caused reversion of the menadione effect on both intestinal calcium absorption and alkaline phosphatase activity. In conclusion, menadione shifts the balance of oxidative and reductive processes in the enterocyte towards oxidation causing deleterious effects on intestinal Ca(2+) absorption and associated variables, which could be prevented by administration of oral glutathione monoester.     

The response of the small intestine to vitamin D. Correlation between calcium-binding-protein production and increased calcium absorption

1. The synthesis of calcium-binding protein, a protein produced in the small intestine in response to vitamin D, was investigated with a view to determining whether calcium-binding-protein production could be correlated with the stimulation of calcium absorption by vitamin D. 2. A radioimmunological assay, which can quantitatively estimate calcium-binding-protein concentrations as low as 1μg/g wet wt., was used to detect the synthesis of soluble calcium-binding protein. 3. When used on intestinal supernatants from chicks dosed with vitamin D, calcium-binding protein was not detectable at 8h but was present after 12h at a concentration of 8.6μg/g wet wt.; in agreement with this an increase in calcium absorption due to vitamin D was detected at 12h but not at 8h. 4. The synthesis of calcium-binding protein was also monitored directly by making use of the ability of the iodinated antiserum to bind specifically to nascent calcium-binding protein chains on intestinal polyribosomes; in this way calcium-binding-protein synthesis could be detected 8h after dosage with vitamin D. Further, the binding reaction indicated a near linear increase in the calcium-binding-protein-synthesizing capacity over a 16h period. 5. From the amount of calcium-binding protein present 12 and 24h after vitamin D administration it is calculated that calcium-binding-protein mRNA is produced at approx. 1mol/min per intestinal cell. 6. It is concluded that the high correlation between the initiation of calcium-binding-protein synthesis and the stimulation of calcium absorption by vitamin D strengthens the proposal that calcium-binding protein plays an important role in calcium transport.     

Calcium absorption in corticoid treated subjects effects of a single oral dose of calcitriol

We compared the fractional absorption of calcium (FACa, 6 h, % TD) and the radiocalcium transit (% TD per min) in seven glucocorticoid-treated patients (10-25 mg prednisolone per day) and in seven normal subjects, in the basal state and 12 h after an oral dose of synthetic 1,25-(OH)2D (3 micrograms). In the basal state, the radiocalcium transit was significantly decreased (P less than 0.02) at 15 min in patients treated with prednisolone, but FACa at 6 h was not significantly decreased (51 +/- 5 vs. 60 +/- 5% TD). 12 h after an oral dose of 1,25-(OH)2D which resulted in supraphysiologic plasma levels, FACa increased significantly (P less than 0.02) in both groups but the peak absorption rate of Ca remained lower in the corticoid-treated patients than in controls (P less than 0.02). The results suggest that glucocorticoids decrease the 1,25-(OH)2D-dependent transport of calcium across the proximal small intestine.     

Effect of aluminium on duodenal calcium transport in pregnant and lactating rats treated with bromocriptine

The aim of present work was to study the effect of oral aluminium (Al) overload on intestinal calcium (Ca) absorption in the critical stages of pregnancy and lactation of rats and to find out possible relationships with prolactin (PRL) and 17beta-estradiol (E2) circulating levels. Adult female Wistar rats were orally treated from day 1 of pregnancy with 0 (control), or 50 mg elemental Al (as chloride)/kg body weight per day. Ca transport was determined by everted duodenal sacs technique using 2 microCi of (45)CaCl(2) as flux marker (JCa(ms)). Al treatment reduced JCa(ms) either in late pregnancy (day 19) or in middle lactation (day 9 postpartum). Oral administration of bromocriptine (BrC), an inhibitor of PRL secretion, at dose of 10 mg/kg body weight given 18 h before JCa(ms) measurements were done, produced a significant decrease in the inhibitory effect of Al on JCa(ms), expressed as percent of control, at day 9 of nursing (vehicle: 51+/-7%, BrC: 28+/-4%, P <0.05). A positive correlation between Al effects on JCa(ms) and the physiological variations of E2 serum levels along pregnancy and lactation in BrC-treated rats was also found (r(2)=0.277, P =0.001). We conclude Al could reduce transcellular Ca absorption in the duodenum by interfering with physiological mechanisms of Ca transport partially mediated by serum level increments of E2 and PRL, observed in late pregnancy and mainly during middle lactation of rats.     

Mitochondrial dysfunction is responsible for the intestinal calcium absorption inhibition induced by menadione

Menadione (MEN) inhibits intestinal calcium absorption by a mechanism not completely understood. The aim of this work was to find out the role of mitochondria in this inhibitory mechanism. Hence, normal chicks treated with one i.p. dose of MEN were studied in comparison with controls. Intestinal calcium absorption was measured by the in situ ligated intestinal segment technique. GSH, oxidoreductase activities from the Krebs cycle and enzymes of the antioxidant system were measured in isolated mitochondria. Mitochondrial membrane potential was measured by a flow cytometer technique. DNA fragmentation and cytochrome c localization were determined by immunocytochemistry. Data indicate that in 30 min, MEN decreases intestinal Ca(2+) absorption, which returns to the control values after 10 h. GSH was only decreased for half an hour, while the activity of malate dehydrogenase and alpha-ketoglutarate dehydrogenase was diminished for 48 h. Mn(2+)-superoxide dismutase activity was increased in 30 min, whereas the activity of catalase and glutathione peroxidase remained unaltered. DNA fragmentation and cytochrome c release were maximal in 30 min, but were recovered after 15 h. In conclusion, MEN inhibits intestinal Ca(2+) absorption by mitochondrial dysfunction as revealed by GSH depletion and alteration of the permeability triggering the release of cytochrome c and DNA fragmentation.     

Niosomes for oral delivery of nateglinide: in situ–in vivo correlation

Niosomes have been claimed to enhance intestinal absorption and to widen the absorption window of acidic drugs. This was reported after monitoring the intestinal absorption in situ. Accordingly, the aim of this work was to investigate the effect of niosomal encapsulation on intestinal absorption and oral bioavailability of nateglinide. This was conducted with the goal of correlation between in situ intestinal absorption and in vivo availability. The drug was encapsulated into proniosomes. The niosomes resulting after hydration of proniosomes were characterized with respect to vesicle size and drug entrapment efficiency. The in situ rabbit intestinal absorption of nateglinide was monitored from its aqueous solution and niosomes. Streptozotocin was used to induce diabetes in albino rats which were then used to assess the hypoglycemic effect of nateglinide after oral administration of aqueous dispersion and niosomal systems. The prepared vesicles were in the nanoscale with the recorded size being 283?nm. The entrapment efficiency depended on the pH of the formulation. The in situ intestinal absorption reflected non-significant alteration in the membrane transport parameters of the drug after niosomal encapsulation compared with the free drug solution. In contrast, niosomes showed significant improvement in the rate and extent of the hypoglycemic effect compared with the unprocessed drug. This discrepancy can be attributed to different transport pathway for the drug after niosomal inclusion with the vesicles undergoing translymphatic transport which can minimize presystemic metabolism. However, this requires confirmatory investigations. In conclusion niosomes can enhance oral bioavailability of nateglinide with the absorption being through nontraditional pathway.