Differences In Intestinal Absorption Research Articles

Quantitative Prediction of Intestinal Absorption of Drugs from In Vitro Study: Utilization of Differentiated Intestinal Epithelial Cells Derived from Intestinal Stem Cells at Crypts.

Prediction of intestinal absorption of drugs in humans is one of the critical elements in the development process for oral drugs. However, it remains challenging, because intestinal absorption of drugs is influenced by multiple factors, including the function of various metabolic enzymes and transporters, and large species differences in drug bioavailability hinder the prediction of human bioavailability directly from in vivo animal experiments. For the screening of intestinal absorption properties of drugs, a transcellular transport assay with Caco-2 cells is still routinely used by pharmaceutical companies because of its convenience, but the predictability of the fraction of the oral dose that goes to the portal vein of metabolic enzyme/transporter substrate drugs was not always good because the cellular expression of metabolic enzymes and transporters is different from that in the human intestine. Recently, various novel in vitro experimental systems have been proposed such as the use of human-derived intestinal samples, transcellular transport assay with induced pluripotent stem-derived enterocyte-like cells, or differentiated intestinal epithelial cells derived from intestinal stem cells at crypts. Crypt-derived differentiated epithelial cells have an excellent potential to characterize species differences and regional differences in intestinal absorption of drugs because a unified protocol can be used for the proliferation of intestinal stem cells and their differentiation into intestinal absorptive epithelial cells regardless of the animal species and the gene expression pattern of differentiated cells is maintained at the site of original crypts. The advantages and disadvantages of novel in vitro experimental systems for characterizing intestinal absorption of drugs are also discussed. SIGNIFICANCE STATEMENT: Among novel in vitro tools for the prediction of human intestinal absorption of drugs, crypt-derived differentiated epithelial cells have many advantages. Cultured intestinal stem cells are rapidly proliferated and easily differentiated into intestinal absorptive epithelial cells simply by changing the culture media. A unified protocol can be used for the establishment of intestinal stem cell culture from preclinical species and humans. Region-specific gene expression at the collection site of crypts can be reproduced in differentiated cells.

Fecal Microbiota Transplantation Reshapes the Physiological Function of the Intestine in Antibiotic-Treated Specific Pathogen-Free Birds.

The topic about the interactions between host and intestinal microbiota has already caught the attention of many scholars. However, there is still a lack of systematic reports on the relationship between the intestinal flora and intestinal physiology of birds. Thus, this study was designed to investigate it. Antibiotic-treated specific pathogen-free (SPF) bird were used to construct an intestinal bacteria-free bird (IBF) model, and then, the differences in intestinal absorption, barrier, immune, antioxidant and metabolic functions between IBF and bacteria-bearing birds were studied. To gain further insight, the whole intestinal flora of bacteria-bearing birds was transplanted into the intestines of IBF birds to study the remodeling effect of fecal microbiota transplantation (FMT) on the intestinal physiology of IBF birds. The results showed that compared with bacteria-bearing birds, IBF birds had a lighter body weight and weaker intestinal absorption, antioxidant, barrier, immune and metabolic functions. Interestingly, FMT contributed to reshaping the abovementioned physiological functions of the intestines of IBF birds. In conclusion, the intestinal flora plays an important role in regulating the physiological functions of the intestine.

Phytoene Is More Efficiently Absorbed Than Lycopene by In Vitro Intestinal Cells but Is Absorbed and Cleared Similarly to Lycopene by In Vitro Prostate Cancer Cells

ObjectivesConsuming tomatoes and the tomato carotenoid lycopene (LYC) is epidemiologically associated with reduced prostate cancer risk. Tomato carotenoids, including LYC, phytoene (PE), and beta-carotene (BC), are found in human prostate tissue, with greater PE: LYC ratios found in the blood and prostate tissue relative to the diet. We tested the hypothesis that PE is more efficiently absorbed by prostate cells and by absorptive intestinal cells than LYC, explaining the enrichment of PE in blood and prostate tissue. MethodsIn vitro prostate cancer (LNCaP, PC-3) and non-cancerous prostate epithelial (RWPE-1) cells were treated with human serum enriched with PE, LYC, BC, or control (final media concentration 1 uM) for 6 hours. Clearance of PE, LYC, and BC from LNCaP cells was monitored for 48 hours after a 16 hour pre-incubation with carotenoids (n = 5 trials). Differentiated in vitroabsorptive intestinal cells (Caco-2 HTB-37 cultured 21 d on a permeable support) were treated with mixed lipid micelles and either PE, LYC, BC, or no carotenoid (final media carotenoid concentration 2 uM) for 4 or 24 h (n = 5 trials). Cell and media carotenoid concentrations were measured by HPLC-PDA. ResultsPC-3s absorbed 3.8%, 1.9%, and 2.5% (not significantly different, ns) and LNCaP cells absorbed 1.5%, 2.6%, and 2.0% of the LYC, PE, and BC (ns) doses, respectively, while RWPE-1 cells absorbed more of the BC dose (8.7%) than the PE dose (0.4%, P < 0.05), and LYC dose absorption was intermediate and similar to both PE and BC (2.5%). LNCaP cells cleared PE at the same rate as BC and LYC over 48 h. Intestinal Caco-2 cells absorbed more PE dose at 4 and 24 h (16.3%, 10.8%) than LYC (0.6%, 0.9%, respectively) or BC (5.8%, 7.5% respectively) (P < 0.05), while the amount of carotenoid recovered in the basolateral media showed a similar, though non-significantly different, pattern. ConclusionsThese results align with whole body pharmacokinetic findings suggesting that differences in intestinal absorption may be a key determinant in relative tissue carotenoid accumulation, and reveal that cancer versus non-cancer cell types may differ in carotenoid absorption characteristics. Funding SourcesNIH NCCIH/ODS R01 AT008576.

Differences in intestinal absorption of Gegen Qinlian Decoction between normal rats and rats with large intestinal damp-heat syndrome

The study aimed to compare the difference in intestinal absorption of the components of Gegen Qinlian Decoction between normal rats and those with large intestinal damp-heat syndrome in the pathological state, in order to explore the rational application of Gegen Qinlian Decoction in the treatment of large intestinal damp-heat syndrome. Puerarin, daidzin, liquiritin, scutellarin, baicalin, wogonoside, coptisine, jatrorrhizine, berberine and palmatine were used as the detection indexes in the in vitro everted gut sacs absorption experiment. The cumulative absorption amount(Q/μg) and the absorption rate(K_a) of each component in each intestine segment were calculated and compared. It was found that the absorption of each component in different intestinal segments were linear absorption, with R~2 greater than 0.9, which conformed to the zero-order absorption rate. There were differences between normal rats and model rats in the absorption of the components in Gegen Qinlian Decoction with the same concentration. Intestinal absorption of most components of Gegen Qinlian Decoction in the model of large intestinal damp-heat syndrome increased to some extent. The components of Gegen Qinlian Decoction with the concentration of 200 g·L~(-1) had the highest absorption in the jejunum of the model rats, and the absorption in the ileum, duodenum and colon successively decreased except daidzin and baicalin. In terms of the absorption rate constant, the absorption in the duodenum and jejunum were significantly increased(P&lt;0.01) compared with normal rats, and the absorption in the ileum was significantly decreased(P&lt;0.01) compared with normal rats. In addition, the absorption of puerarin, daidzin, glycyrrhizin, coptisine and berberine increased selectivity in the colon. Therefore, pathological model animals were recommended in the study of the components relating to absorption effect, in order to really lay a research foundation for the symptomatic treatment of large intestinal damp-heat syndrome.

Regional difference in intestinal drug absorption as a measure for the potential effect of P-glycoprotein efflux transporters.

The aim of this research was to assess regional difference in the intestinal absorption of ranitidine HCl as an indicator for the potential effect of P-glycoprotein (P-gp) efflux transporters. In situ rabbit intestinal perfusion was used to investigate absorption of ranitidine HCl, a substrate for P-gp efflux from duodenum, jejunum, ileum and colon. This was conducted both in the presence and absence of piperine as P-gp inhibitor. Ranitidine HCl was incompletely absorbed from rabbit intestine. The length normalized absorptive clearance (PeA/L) of ranitidine HCl was ranked as colon>duodenum>jejunum>ileum. This is the reverse order of the magnitude of P-gp expression. Coperfusion of piperine with ranitidine HCl significantly increased the PeA/L of ranitidine HCl from jejunum and ileum with no significant change on the absorption from duodenum and colon. This was confirmed by significant reduction in the length required for complete ranitidine HCl absorption from jejunum and ileum in presence piperine. The results indicate that P-gp transporters play a major role in determining regional difference in intestinal absorption of ranitidine HCl. Thus, the regional absorption of drugs may be taken as an indirect indication for the role of P-gp in intestinal absorption.

Difference in intestinal absorption of Wuzhuyu decoction between normal and migraine model rats

To compare the intestinal absorption of Wuzhuyu decoction(WZYD) between normal rats and migraine model rats, and investigate the optimized WZYD from aspect of absorption. The rat single pass intestinal perfusion test(SPIP) was adopted for optimized sample and un-optimized sample in normal and migraine model rats induced by nitroglycerin and reserpine. The contents of 8 ingredients were determined by high performance liquid chromatography(HPLC), and 4 absorption parameters for each ingredient were calculated and compared: unit area absorption(Mper area), absorption rate constant(Ka), apparent coefficient(Papp) and relative absorption rate(RA). The results showed that there was a great difference between normal rats and model rats in the intestinal absorption of the same WZYD. As compared with normal rats, the absorption parameters of most ingredients in optimized sample were increased in migraine model rats induced by nitroglycerin; Similar phenomena were also found in migraine model rats induced by reserpine. However, the absorption parameters of most ingredients were decreased in un-optimized sample. Therefore, pathological model rats shall be used for effective ingredient recognition based on the correlation between intestinal absorption spectra and pharmacological effects. As compared with the un-optimized samples, the absorption of effective ingredients was faster, easier and more adequate in the optimized samples, revealing their mechanism on better efficacy from the aspect of absorption.

Secretory and absorptive dysfunctions in ob/ob mouse jejunum are sex‐dependent (1117.1)

Sex‐dependent differences in intestinal absorption and intestinal secretion in the ob/ob leptin‐deficient obese mouse are poorly understood. We used male and female ob/ob and lean mice aged ~14 weeks. The goal of this study was to characterize jejunal function in this clinically relevant mouse model. We measured transepithelial short circuit current (Isc), a measure of chloride secretion, across freshly isolated segments of jejunum from ob/ob and lean mice. Compared to lean controls, basal Isc was significantly decreased by 24 µA/cm2 (P&lt;0.05, n=9) in ob/ob females and significantly decreased by 30 µA/cm2 (P&lt;0.05, n=10‐11) in ob/ob males. Reduced basal Isc in ob/ob males is partly attributed to a significant 2‐fold decrease in CFTR expression. The contribution of key transporters involved in promoting chloride secretion are currently under evaluation. While crypt depth was unchanged in ob/ob males, the number of goblet cells/crypt was 2‐fold greater and this may also account for, in part, the reduced basal Isc in ob/ob males. Villi length and total small intestinal length were both significantly increased in ob/ob female and male mice, suggesting a greater surface area for absorptive function. These structural changes likely contribute towards the obese phenotype. Expression of the fructose transporter protein, GLUT5 (normalized to GAPDH), was significantly increased 1.9‐fold (P&lt;0.05, n=12‐15) in male ob/ob mice compared to leans, which likely contributes to the diabetic/obese phenotype of ob/ob males. Expression of the glucose co‐transporter protein, SGLT1 (normalized to GAPDH), was significantly decreased 30% (P&lt;0.05, n=8‐9) in female ob/ob mice compared to leans. These data suggest that basal jejunal Isc in ob/ob mice is deficient, and may contribute towards slower transit times in the gastrointestinal tract in the ob/ob mice. Interestingly, while both female and male ob/ob mice are obese, the specific secretory and absorptive dysfunctions are not comparable in both sexes.Grant Funding Source: Supported by NIH R15 DK071625‐01A2

Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal epithelial cells

Fexofenadine contains a chiral carbon in its chemical structure and is orally administered as a racemic mixture. This study evaluated the selective uptake of fexofenadine enantiomers by Caco-2 cells as a model of intestinal epithelial cells. R(+)-fexofenadine or S(-)-fexofenadine was applied to Caco-2 cells, followed by incubation. After incubation, the amounts of fexofenadine enantiomers in cells were determined. The kinetic parameters for the uptake of fexofenadine enantiomers by Caco-2 cells were estimated using the Michaelis-Menten equation. The transporter-mediated uptake rate of R(+)-fexofenadine was 1.7-fold higher than that of S(-)-fexofenadine. The difference in transporter-mediated R(+)-fexofenadine and S(-)-fexofenadine uptake was completely diminished under ATP-depleted conditions and in the presence of organic anion transporter peptide (OATP) inhibitors. Also, a Dixon plot showed that each fexofenadine enantiomer was competitively inhibited by the other enantiomer. The ratio of R(+)-fexofenadine uptake to S(-)-fexofenadine uptake in the case of a racemic mixture was higher than that in the case of a single enantiomer. This study suggested that the selective absorption of fexofenadine enantiomers by intestinal epithelial cells might have been due to the selective uptake mediated by OATPs and that the difference in intestinal absorption was enhanced with a racemic mixture.

Changes in the pharmacokinetics of glibenclamide in rats with streptozotocin-induced diabetes mellitus

The aim of this study was to investigate the pharmacokinetics of glibenclamide (Gli) administrated orally and intravenously to normal and diabetic rats. The AUC(0–720min) of orally administered Gli in diabetic rats (321.24mgmin/L) was greater than that (57.752mgmin/L) in normal rats. CL (0.019L/min/kg) was significantly slower than that (0.092L/min/kg) of normal rats. The AUC(0–480min) of intravenous Gli in diabetic rats (1528.280mgmin/L) also was significantly greater than that (509.523mgmin/L) in normal rats, and CL was decreased approximately 3-fold. No significant difference in intestinal absorption of Gli was observed between normal and diabetic rats as determined by in situ single-pass intestinal perfusion. The clearance of Diclofenac (a substrate of CYP2C9) was determined to evaluate changes in hepatic drug-metabolizing enzyme activity in rats. The CL in diabetic rats was significantly lower (42.43% decrease) than that in normal rats. Hepatic protein expression of CYP2C9 was measured using Western blot analysis; compared with normal rats, the hepatic protein expression of CYP2A9 was decreased in diabetic rats. Therefore, the slower clearance of Gli in diabetic rats can be attributed primarily to the lower expression of hepatic CYP2C9.

Morphology and enzymatic activity of the small intestinal mucosa of Iberian pigs as compared with a lean pig strain1

Castrated male Iberian (n = 12) and Landrace × Large White (n = 12) pigs were used to study histological structure and enzymatic activity in the small intestine at 3 points of the productive cycle (BW = 15, 50, and 115 kg). Both strains were fed the same cereal-based diets (DE = 2,799 kcal·kg(-1), and CP = 15%) throughout the entire experimental period. Differences (P < 0.05) in histometrical variables (villus height, width and surface, crypt depth, villus height/crypt depth relationship, mucosal thickness, muscular layer thickness, and number of goblet cells) were found among samples of small intestinal sections (duodenum, jejunum, and ileum) at the 3 productive stages studied. Also, differences (P < 0.05) in histometrical variables of small intestinal samples were found between Iberian and lean pigs at all productive stages, although these differences tended to disappear with age. Differences (P < 0.05) in enzymatic activities (lactase, sucrase, maltase, isomaltase, aminopeptidase, and alkaline phosphatase) of small intestinal samples were found between the different intestinal sections at all productive stages studied. Although differences (P < 0.05) in enzymatic activities of small intestinal samples were found between Iberian and lean pigs at all productive stages, values tended to equalize with pig age. We concluded that differences previously found in dietary nutritional utilization between Iberian and lean strains are likely not due to differences in intestinal absorption or hydrolytic capacity.

Effects of cis‐9, trans‐11 and trans‐10, cis‐12 CLA isomers on liver and adipose tissue fatty acid profile in hamsters

The aim of the present study was to investigate the effect of cis-9,trans-11 and trans-10,cis-12 CLA on FA composition of TAG in epididymal adipose tissue and liver, and of hepatic phospholipids PL. Twenty-four Syrian Golden hamsters were randomly divided into three groups of eight animals each and fed semipurified atherogenic diets supplemented with either 0.5 g/100 g diet of linoleic acid or cis-9,trans-11 or trans-12,cis-9 CLA for 6 wk. Total lipids were extracted, and TAG and PL were separated by TLC. FA profile in lipid species from liver and adipose tissue, as well as in feces, was determined by GC. Trans-10,cis-12 CLA feeding significantly reduced linoleic and linolenic acids in TAG from both tissues, leading to reduced total PUFA content. Moreover, in the epididymal adipose tissue docosenoic and arachidonic acids were significantly increased. In liver PL, although no changes in individual FA were observed, total saturated FA (SFA) were decreased. No changes in TAG and PL FA profiles were induced by the cis-9,trans-11 CLA. TAG and PL incorporated cis-9,trans-11 more readily than trans-10,cis-12 CLA. This difference was not due to differential intestinal absorption, as shown by the analysis of feces. We concluded that only trans-10,cis-12 CLA induces changes in FA composition. Whereas increased PUFA content was observed in either liver or adipose tissue TAG, decreased SFA were found in liver PL. Incorporation of cis-9,trans-11 CLA in TAG is greater than that of trans-10,cis-12 CLA, but this is not due to differences in intestinal absorption.

Factors influencing regional differences in intestinal absorption of UK-343,664 in rat: Possible role in dose-dependent pharmacokinetics

The objective of this study was to evaluate potential contributions of intestinal export and metabolism to the oral dose-dependent pharmacokinetics of the human cGMP-specific phosphodiesterase type 5 inhibitor, UK-343,664. Differences between jejunal and ileal handling of this CYP3A and P-gp substrate were investigated. CYP3A and P-gp display differing activities in the upper and lower mammalian small intestine and their impact on variable drug absorption can be mechanistically assessed for individual compounds with in situ perfusion of rat's small intestine. Isolated segments of rat jejunum and ileum were perfused with UK-343,664 solution and measurements were made as a function of drug concentration for dose dependence and in the presence of CYP3A and P-gp inhibitors. Intestinal permeability and metabolism were measured by total drug disappearance and major metabolite, UK-347,334 (N-desethyl metabolite), appearance in the intestinal lumen. Intestinal tissue and mesenteric blood measurements of drug and metabolite were also determined. The effective permeability (Peff) of UK-343,664 and metabolite formation (Fmet) increased as a function of concentration. Regional differences in Peff and Fmet were observed with low-intestinal metabolism of UK-343,664 in both regions (<10%). P-gp inhibition caused significant increase in Peff and Fmet in jejunum and ileum while ketoconazole, a P-gp and CYP3A inhibitor, has only limited effect on metabolism. In conclusion, UK-343,664 absorption is mainly regulated by P-gp in jejunum and ileum while CYP3A intestinal metabolism has minimal effect. This role of P-gp could explain the dose-dependent pharmacokinetics of UK-343,664 and its unusual behavior of tmax as a function of dose. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Relationship between dietary iron intake, corrected for diet reporting error, and serum ferritin in Danish women aged 35-65 years.

Several studies have failed to demonstrate an association between Fe status and intake of dietary Fe. However, in the long term, it seems logical to presume that body Fe reserves are, fundamentally, dependent on the intake of bioavailable dietary Fe. This discrepancy may depend on several factors: (1) interindividual variation in biological availability of dietary Fe (differences in intestinal absorption), (2) interactions between dietary Fe and absorption enhancers and inhibitors, (3) variations in physiological (menstruation, childbirth) or unphysiological (blood donation) Fe losses, (4) the failure to adjust dietary intake data for Fe supplements, (5) uncertain food composition data (discrepancies between calculated and chemically measured Fe content in the diet), and (6) diet reporting error (reported intake of dietary Fe may deviate considerably from the true intake). The present study examined associations between dietary intake of Fe (assessed by diet history interview) and Fe status (assessed by ferritin status) among 167 Danish women aged 35-65 years, who were not blood donors, by taking into account diet reporting error (assessed from p-amino benzoic acid-validated urinary N), physiological blood losses (menstruation, childbirth, abortions), and Fe supplementation. Our results indicate that the lack of a general association between Fe status and dietary Fe intake may, in part, be caused by selective diet reporting error.

Intestinal absorption and renal excretion of dietary methionine sources by the growing chicken

The biopotency of DL-methionine (MET) and 2-hydroxy-4-[methylthio]butanoic acid (DL-HMB) for broiler chicks was determined using a semipurified diet. Based on growth rate and efficiency of feed utilization, DL-HMB was 72% as potent as DL-MET, while the potencies of L-MET and DL-MET were not different. Studies were conducted to determine if differences in intestinal absorption or urinary excretion of these compounds account for differences in bioavailability. 14C-labeled methionine sources were fed to 2- to 3-week-old broiler chicks and the extent of their absorption determined using Cr 2O 3 as a marker of digestibility. All three sources were completely absorbed in the small intestine. Urinary excretion was studied in 4- to 6-week-old broiler chicks. Saline solutions containing inulin, and 20 mmol/L L-MET, 20 mmol/L D-MET, or 5 or 20 mmol/L DL-HMB were infused intravenously. Blood and urine samples were taken at regular intervals over a 50-min period. The plasma concentrations of L-MET, D-MET, and DL-HMB increased during the course of infusion to 0.5 mmol/L. Urinary excretion of L-MET and D-MET remained less than 1% and 2.2% of the filtered load, respectively. Excretion of HMB increased from about 6% to about 18% of the filtered load as plasma concentration increased to about 0.3 mmol/L, and increased abruptly at higher plasma concentrations. Based on these data and plasma HMB concentrations determined in chicks fed DL-HMB, urinary losses of HMB would be less than 1% of the daily intake. These experiments indicate that differences of biopotency between methionine sources are not due to variations in intestinal absorption or urinary excretion.

Demonstration of a difference in urinary calcium, not calcium absorption, in black and white adolescents

Bone mineral density (BMD) of the forearm, lumbar spine, and femoral neck is greater in black than in white children. Studies were performed to determine whether differences in intestinal absorption of calcium or urinary calcium or both account for an assumed more positive calcium balance and greater bone mass in black children. Normal black and white boys and girls were admitted to a metabolic ward and given a constant daily diet containing 1000 mg calcium, 60% as calcium carbonate, for 2 1/2 days (study I) or 3 1/2 days (study II). Fasting blood and 24 h urine collections were obtained, and in study II, unidirectional fractional absorption of calcium (alpha) was determined with stable isotopes of calcium. It was found that (1) serum 25-hydroxyvitamin D (25-OHD) and urinary calcium were lower and serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] was higher in black than in white children, and (2) alpha was higher in boys than in girls with no racial difference, and (3) there were significant positive correlations between alpha and urinary calcium in the blacks and in the black and white children together. It is concluded that (1) alpha is higher in boys than in girls and (2) a lower urinary calcium, not increased intestinal absorption of calcium, is the means for a more positive calcium balance in blacks that accounts for the racial difference in BMD.

Intestinal Absorption of Calcium and Calcium Metabolism in Patients With Essential Hypertension and Normal Renal Function

Several abnormalities of calcium metabolism have been described in patients with essential hypertension, and they have been linked to the pathogenesis of hypertension. Intestinal calcium absorption has been shown to be decreased in rats with spontaneous hypertension, but it has not been studied in patients with essential hypertension. In these studies we have for the first time measured intestinal absorption of calcium (using oral and intravenous administration of 47Ca), along with other parameters of calcium metabolism, in 14 patients with essential hypertension and normal renal function and in 16 normal subjects. There was no difference in serum total or ionized calcium, serum phosphorus, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxy-vitamin D(24,25(OH)2D) among hypertensives and normotensives. The urinary excretion of calcium, on the other hand, was greater in hypertensive than in normotensive subjects (195 +/- 33 v 107 +/- 13 mg/24 h, P less than .05). There was also no difference in intestinal absorption of calcium after 2 and 24 h among hypertensives and normotensives. When hypertensive patients were stratified according to plasma renin activity (PRA) we found that patients with low PRA had higher intestinal absorption of calcium at 2 h (23 +/- 2.9 v 18 +/- 0.6%, P less than .05) but not at 24 h. Serum total and ionized calcium, PTH, and 1,25(OH)2D were not different between patients with low and those with normal-high PRA. The major derangement of calcium metabolism in patients with essential hypertension is hypercalciuria. This abnormality is more pronounced in patients with low PRA, and it may lead to increased vitamin D-dependent intestinal absorption of calcium.

Clinical Trial of Modified Whole Milk, Lactose-Hydrolyzed Whole Milk, or Cereal-Milk Mixtures for the Dietary Management of Acute Childhood Diarrhea

A randomized, double-masked clinical trial was completed to compare the effects of four dietary regimens for the nutritional management of 116 Peruvian children between 3 and 24 months of age with acute diarrhea. Diets consisted of a modified whole milk formula (group M), a lactose-hydrolyzed milk formula (HM), wheat noodles and whole milk (N-M), or wheat noodles and lactose-hydrolyzed whole milk (N-HM), all offered in amounts up to 55 kcal/kg body weight/day for the first 2 days of treatment and up to 110 kcal/kg/day for 4 days thereafter. The clinical characteristics of the patients in each group were similar initially. Treatment failure rates in the two milk groups combined (M = 14.3%, HM = 20.0%) were greater than in the two noodle-milk groups combined (N-M = 3.4%, N-HM = 3.4%), p = 0.03. The average stool outputs by children in both M groups (range 40-66 g/kg body weight per day on all study days) were consistently greater than those by children in both N-M groups (range 29-50 g/kg/day). The differences by dietary group were statistically significant on days 3 and 4 (p less than 0.04, analysis of variance). The estimated median durations of illness [and 95% confidence limits (CL)] in each milk group (M = 138 h, CL: 88-214; HM = 113 h, CL: 75-170) were significantly greater than in each noodle-milk group (N-M = 52 h, CL: 35-76; N-HM = 67 h, CL: 45-100), p less than 0.001-0.071. In this group of patients, noodle-milk mixtures produced fewer treatment failures, lower fecal outputs, and shorter durations of diarrhea than did milk alone, regardless of the lactose contents of the respective milks or mixed diets. Small differences in intestinal absorption and changes in body weight by dietary group that were identified were of minor clinical importance during the short duration of study. Thus, the noodle-milk diets employed during this study were safer than the milk diets for the dietary management of children with acute diarrhea.

Clinical Trial of Modified Whole Milk, Lactose‐Hydrolyzed Whole Milk, or Cereal‐Milk Mixtures for the Dietary Management of Acute Childhood Diarrhea

SummaryA randomized, double‐masked clinical trial was completed to compare the effects of four dietary regimens for the nutritional management of 116 Peruvian children between 3 and 24 months of age with acute diarrhea. Diets consisted of a modified whole milk formula (group M), a lactose‐hydrolyzed milk formula (HM), wheat noodles and whole milk (N‐M), or wheat noodles and lactose‐hydrolyzed whole milk (N‐HM), all offered in amounts up to 55 kcal/kg body weight/day for the first 2 days of treatment and up to 110 kcal/kg/day for 4 days thereafter. The clinical characteristics of the patients in each group were similar initially. Treatment failure rates in the two milk groups combined (M = 14.3%, HM = 20.0%) were greater than in the two noodle‐milk groups combined (N‐M = 3.4%, N‐HM = 3.4%), p = 0.03. The average stool outputs by children in both M groups (range 40–66 g/kg body weight per day on all study days) were consistently greater than those by children in both N‐M groups (range 29–50 g/kg/day). The differences by dietary group were statistically significant on days 3 and 4 (p &lt; 0.04, analysis of variance). The estimated median durations of illness [and 95% confidence limits (CL)] in each milk group (M = 138 h, CL: 88–214; HM = 113 h, CL: 75–170) were significantly greater than in each noodle‐milk group (N‐M = 52 h, CL: 35–76; N‐HM = 67 h, CL: 45–100), p &lt; 0.001–0.071. In this group of patients, noodle‐milk mixtures produced fewer treatment failures, lower fecal outputs, and shorter durations of diarrhea than did milk alone, regardless of the lactose contents of the respective milks or mixed diets. Small differences in intestinal absorption and changes in body weight by dietary group that were identified were of minor clinical importance during the short duration of study. Thus, the noodle‐milk diets employed during this study were safer than the milk diets for the dietary management of children with acute diarrhea.

Origin of regional and species differences in intestinal glucose uptake.

Differences in intestinal absorption among physiological states, intestinal regions, and animal species could arise from many anatomical factors (e.g., intestinal length and diameter, or area amplification by villi and microvilli) and biochemical factors (e.g., transporter density and turnover number). In no comparison had all these factors been measured. Hence we made the necessary new measurements to identify the origin of differences in glucose absorption among three species (mouse, desert wood rat, and desert iguana) and among three intestinal regions in two of these species. Turnover numbers range from 6,900 to 32,300 glucose molecules per minute per site. Microvilli amplify intestinal area by a larger factor (36-96 times) than do villi (2-14 times), so that the intestine's actual area is at least 110-1,280 times the nominal area of the equivalent smooth-bore cylinder. Species comparisons among mammals yield the striking result that the area of the whole length of the small intestine at the microvillus level varies nearly linearly as the mammal's metabolic live mass. For the species studied, all the anatomical and biochemical factors studied proved to make significant contributions to species and regional difference in glucose uptake.

Evidence that low plasma 1,25-dihydroxyvitamin D causes intestinal malabsorption of calcium and phosphate in juvenile X-linked hypophosphatemic mice.

X-linked hypophosphatemic (Hyp) mice are a model for human sex-linked vitamin D-resistant rickets. We have reported intestinal malabsorption of calcium in young Hyp mice, and in this report we have explored the mechanism for it. To test for resistance of the intestine to 1,25(OH)2 vitamin D3, this hormone was continually infused via osmotic minipumps into 4-week-old normal and Hyp mice at 0, 17, 50 or 150 ng/kg/day. After 3 days, 45Ca and inorganic 32P were administered by gavage, and the mice were sacrificed on the fifth day. The Hyp mice showed responses to the hormone equivalent to the normal mice in terms of increased intestinal absorption of both 45Ca and 32P, increased plasma isotope levels, increased femoral isotope content, and increased duodenal and renal 9 kD vitamin D-dependent calcium-binding protein (calbindin-D9K; CaBP). Plasma 1,25(OH)2D was measured in these mice. There were significant correlations of plasma 1,25(OH)2D to the intestinal absorption of 45Ca and 32P and to duodenal and renal CaBP. Plasma 1,25(OH)2D was also measured in stock normal and Hyp mice and was found to be lower in 4-week-old Hyp mice than in 4-week-old normal mice (113 +/- 10 pM (n = 18) vs. 67 +/- 10 (n = 20), normal vs. Hyp, p less than .01), but unchanged at 13 weeks of age (77 +/- 13 (n = 13) vs. 70 +/- 15 (n = 15), NS). This observed difference in plasma 1,25(OH)2D between normal and Hyp mice at 4 weeks of age was sufficient to explain the observed normal-to-Hyp differences in intestinal absorption of 45Ca and duodenal and renal CaBP. It also explained 72 +/- 18% of the observed difference in 32P absorption. We conclude that Hyp mouse intestine is not resistant to 1,25(OH)2D and that the lower plasma 1,25(OH)2D of 4-week-old Hyp mice causes intestinal malabsorption of calcium and phosphate.