Effectiveness of submicronized chitosan-coated liposomes in oral absorption of indomethacin

The plasma profile of indomethacin (IMC) after oral administration of IMC-loaded submicronized chitosan-coated liposomes (ssCS-Lip) was evaluated to reveal the effectiveness of the mucoadhesive function for improving the absorption of this poorly absorbable drug. The stomach and small intestine were removed from rats after 1, 2, and 4 hours of oral administration of submicron-sized liposomes (ssLip) or ssCS-Lip containing fluorescent dye, and the retentive properties were confirmed by measuring the amount of dye in each part of the gastrointestinal (GI) tract. Results showed that ssCS-Lip tended to be better retained in the upper part of the GI tract, compared with ssLip, at 1, 2, and 4 hours after administration, and was significantly better retained in the small intestine at 4 hours. The plasma profile and bioavailability of IMC after oral administration of both types of liposomes were improved, compared with oral administration of IMC solution. The maximum residence time of ssCS-Lip was significantly longer than those of ssLip. The extended plasma profile of ssCS-Lip was attributed to its prolonged retention in the upper region of the GI tract, and its delayed migration to the lower part of the intestine, the neutral pH of which is more soluble for IMC, an acidic drug. Therefore, the chitosan-coated ssLip, with its higher retention in the GI tract, is a promising drug carrier for the oral administration of poorly absorbed compounds.     

Effects of juice from Morinda citrifolia (Noni) on gastric emptying in male rats

The effects of juice from Morinda citrifolia (noni) on gastric emptying, gastrointestinal transit, and plasma level of cholecystokinin (CCK) in rats were studied. Male rats were given noni by gavage at levels of 0.25, 1, or 4 ml/kg once per day for one or 7 days. The rats in the control group were given water, while the rats in the experimental group were fasted overnight before measurement of gastrointestinal motility. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal (10%) and Na251CrO4 (0.5 microCi/ml). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Then, gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Finally, blood samples were collected for measurement of CCK by radioimmunoassay. The administration of noni at 0.25 ml/kg, but not at 1 ml/kg and 4 ml/kg, for 1 day significantly inhibited gastric emptying. In contrast, gastric emptying was significantly inhibited by oral noni (0.25, 1, or 4 ml/kg) for 7 days. Intraperitoneal injection of lorglumide (5 or 10 mg/kg), a selective CCK1 receptor antagonist, effectively attenuated the noni-induced inhibition of gastric emptying. The intestinal transit and body weight, food intake, water intake, urine volume as well as feces weight were not altered by the administration of noni either acutely or chronically, but the administration of oral noni (1 ml/kg) for 7 days increased the level of plasma CCK in male rats. These results suggest that oral noni inhibits gastric emptying in male rats via a mechanism involving stimulation of CCK secretion and CCK1 receptor activation.     

Intestinal Distribution and Intraluminal Localization of Orally Administered Clostridium butyricum in Rats

Clostridium butyricum has been used as a probiotic in animals and humans for years, however, its fate in the intestine has not been clarified yet. We investigated the intestinal fate of C. butyricum using a selective medium and a monoclonal antibody after orally administering C. butyricum spores to rats. The number of C. butyricum, both viable and dead cells, in the intestinal contents were counted by enzyme-linked immunosorbent assay (ELISA) at various times after a single oral administration. The total viable number of C. butyricum was counted using a selective medium, and viable resting spores were selectively detected by treating the samples with ethanol. To investigate the intraluminal localization of the C. butyricum cells, frozen intestinal tracts were imprinted onto slides and stained with immunogold-silver. Total viable spores exceeded the number of viable resting spores by more than 10-fold from the proximal to middle of the small intestine 30 min after administration. Vegetative cells of C. butyricum were first detected in the distal small intestine after 2 hr, and vegetative growth was observed from the cecum to the colon 5 hr after administration. Dead vegetative cells were detected 9 hr after administration, and C. butyricum cells were not detected in the intestine after 3 days. The C. butyricum cells in the intestinal imprints were stained specifically by immunogold-silver staining, and proliferative cells were observed in the cecum after 3 hr. These results suggest that the administered C. butyricum germinated in the upper small intestine, grew mainly from the distal small intestine to the colon and were excreted from the rat intestine within 3 days.     

Effectiveness of submicronized chitosan-coated liposomes in oral absorption of indomethacin

The plasma profile of indomethacin (IMC) after oral administration of IMC-loaded submicronized chitosan-coated liposomes (ssCS-Lip) was evaluated to reveal the effectiveness of the mucoadhesive function for improving the absorption of this poorly absorbable drug. The stomach and small intestine were removed from rats after 1, 2, and 4 hours of oral administration of submicron-sized liposomes (ssLip) or ssCS-Lip containing fluorescent dye, and the retentive properties were confirmed by measuring the amount of dye in each part of the gastrointestinal (GI) tract. Results showed that ssCS-Lip tended to be better retained in the upper part of the GI tract, compared with ssLip, at 1, 2, and 4 hours after administration, and was significantly better retained in the small intestine at 4 hours. The plasma profile and bioavailability of IMC after oral administration of both types of liposomes were improved, compared with oral administration of IMC solution. The maximum residence time of ssCS-Lip was significantly longer than those of ssLip. The extended plasma profile of ssCS-Lip was attributed to its prolonged retention in the upper region of the GI tract, and its delayed migration to the lower part of the intestine, the neutral pH of which is more soluble for IMC, an acidic drug. Therefore, the chitosan-coated ssLip, with its higher retention in the GI tract, is a promising drug carrier for the oral administration of poorly absorbed compounds.     

缬沙坦对动脉粥样硬化兔血清IL-8和TNF-α水平的影响

目的：研究缬沙坦对动脉粥样硬化兔血清IL-8和TNF-α水平的影响。方法：将30只实验兔随机分为3组,每组10只,即正常对照组：喂以普通饲料;高脂饮食组：喂以高脂饮食（含15%蛋黄粉,0.5%胆固醇和5%猪油的饲料）6周,后给予10 ml/d生理盐水4周;药物干预组：喂以高脂饮食6周,后给予缬沙坦（10 mg/kg/d）治疗4周。饲养6周和10周时分别经兔耳缘静脉取血,通过酶联免疫法检测各组兔血清中IL-8和TNF-α的水平。结果：饲养第6周时,高脂饮食组和药物干预组兔血清TNF-α和IL-8水平均较正常对照组明显升高,差异均具有统计学意义（P〈0.05）,而高脂饮食组与药物干预组比较差异无统计学意义（P〉0.05）。饲养第10周时,即缬沙坦干预4周后,药物干预组与建模6周时比较,血清TNF-α及IL-8水平均明显下降,差异具有统计学意义（P〈0.05）,且与高脂饮食组比较,血清TNF-α及IL-8水平亦明显下降,差异具有统计学意义（P〈0.05）。结论：动脉粥样硬化时,血清IL-8和TNF-α升高,缬沙坦能明显降低动脉粥样硬化中IL-8和TNF-α水平,从而发挥抗动脉粥样硬化作用。     

Gastrointestinal stability and absorption of insulin in suckling pigs

Stability and absorption of orally administered fluorescein-isothiocyanate labeled insulin (FITC-insulin) in the gastrointestinal (GI) tract were investigated in newborn and 3-day-old pigs. The uptake of FITC-insulin by the intestinal epithelial cells was visualized using confocal laser scanning microscopy. Following oral administration, 3 h later 56 and 88% of orally administered fluorescence was found in the GI tract in newborn and 3-day-old piglets, respectively. Chromatographic analysis revealed that 15-37% of fluorescence recovered from the gastric and proximal intestinal contents was eluted in the void volume of a Sephadex G-25 column. It was also observed that oral administration of FITC-insulin at a dose of 100 nmol/kg body weight led to a significant decrease in blood glucose in newborn pigs (P<0. 05) but not in 3-day-old pigs. Microscopic examination showed that FITC-insulin was taken up via the vesicular transport mechanism throughout the whole small intestine but the ileum appeared to be a preferred site for FITC-insulin transport in newborn pigs. In 3-day-old pigs, the uptake of FITC-insulin occurred only in the distal part of the small intestine. These findings suggest that milk-borne insulin may partially survive in the GI lumen and subsequently act on the gastrointestinal tract in suckling piglets, while GI absorption of milk-borne insulin is limited to newborn pigs.     

Release of peptide YY by fat in the proximal but not distal gut depends on an atropine-sensitive cholinergic pathway

Peptide YY (PYY) is released when PYY cells in short term culture are exposed to fat suggesting that this peptide may be released by fat in the distal gut without neural stimulation. PYY is also released by fat in the proximal 1/2 of small intestine. To test the hypothesis that the release of PYY by fat in the proximal but not distal intestine may depend on an atropine-sensitive, cholinergic pathway, PYY levels were compared in four dogs equipped with duodenal and mid-intestinal fistulas when 60 mM oleate was perfused into either the proximal (between fistulas) or distal (beyond mid-intestinal fistula) 1/2 of gut at 2 ml/min for 120 min with intravenous administration of saline or atropine. We found that, when fat was confined to the proximal 1/2 of the intestine, PYY release was reduced following intravenous atropine when compared with saline (p<0.01). However, when fat was confined to the distal 1/2 of the intestine, PYY release was not affected by the intravenous atropine. We conclude that PYY release by fat in the proximal but not distal intestine depends on an atropine-sensitive, cholinergic pathway.     

The selective uptake and transmission of proteins to the circulation from the small intestine of the sucling rat

The relative concentration of various immunoglobulins attained in the sera of 14-day-old rats have been compared 4 h after their oral and intraluminal administration.The circulatory concentration of these proteins attained higher values when they were administered into the isolated proximal small intestine than when they were administered into the distal small intestine. Selective uptake of proteins was shown to predominate in the proximal small intestine.     

Digestion and Gastrointestinal Absorption of the 14–16-kDa Rice Allergens

The digestibility and gastrointestinal absorption of 14–16-kDa rice allergens (RAs) were investigated. RAs and bovine serum albumin (BSA) were first evaluated for their digestibility. BSA was digested completely by in vitro incubation with some proteases, but RAs remained almost intact. Administered orally (20 mg per mouse), intact RAs were clearly detected in the small intestine even 60 min after the administration, the amount of total RAs in the small intestine being estimated to be 0.59 mg. RAs were then biotinylated and infused into the duodenal lumen of anesthetized mice, and portal blood was collected. The RA concentrations in the portal plasma were respectively estimated to be 0.4–0.9 and 0.3–2.5 μg/ml for 0.4 and 4 mg doses. These results suggest that RAs are highly resistant to digestive enzymes and that about 1/100 of orally administered RAs remain intact in the small intestine, while at least 1/1,000–1/10,000 is absorbed and delivered into circulated blood.     

Digestion and gastrointestinal absorption of the 14-16-kDa rice allergens

The digestibility and gastrointestinal absorption of 14-16-kDa rice allergens (RAs) were investigated. RAs and bovine serum albumin (BSA) were first evaluated for their digestibility. BSA was digested completely by in vitro incubation with some proteases, but RAs remained almost intact. Administered orally (20 mg per mouse), intact RAs were clearly detected in the small intestine even 60 min after the administration, the amount of total RAs in the small intestine being estimated to be 0.59 mg. RAs were then biotinylated and infused into the duodenal lumen of anesthetized mice, and portal blood was collected. The RA concentrations in the portal plasma were respectively estimated to be 0.4-0.9 and 0.3-2.5 microg/ml for 0.4 and 4 mg doses. These results suggest that RAs are highly resistant to digestive enzymes and that about 1/100 of orally administered RAs remain intact in the small intestine, while at least 1/1,000-1/10,000 is absorbed and delivered into circulated blood.     

Oral administration of recombinant human granulocyte-macrophage colony stimulating factor expressed in rice endosperm can increase leukocytes in mice

Human granulocyte-macrophage colony stimulating factor (hGM-CSF) is used clinically to treat leucopenia typically caused by cancer chemotherapy or radiotherapy. This study used multiple strategies to obtain very high expression levels of OsrhGM-CSF (14 mug/seed) in rice endosperm. Electron micrographs of immunogold-labeled transgenic endosperm showed that rhGM-CSF was not only localized in protein bodies but was also distributed in the apoplast. A biological activity assay indicated that OsrhGM-CSF stimulated the growth of TF-1 cells in vitro. In addition, the transgene was used to effectively treat leucopenia by oral administration of the unprocessed transgenic grains. In cyclophosphamide-induced leucopenic mice, transgenic seeds produced a 27% (t = 0.021) gain in leukocytes after 14 days feeding. Even in non-leucopenic mice, leukocyte gain was 37% (t = 0.002) more than that of mice fed non-transgenic seeds. This study provides a novel approach to the use of oral unprocessed transgenic OsrhGM-CSF seeds to treat leucopenia.     

PYY immunoneutralization does not alter lipid-induced inhibition of gastric emptying in rats

PYY is released from the distal ileum by fat and may be involved in mediating lipid-induced inhibition of gastric acid secretion and intestinal motility. The role of PYY in intestinal lipid-induced inhibition of gastric emptying in awake rats was investigated using a specific polyclonal antibody raised against PYY. METHODS: Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric cannula. Intralipid (total dose 50 or 100 mg) was perfused for 10 min (0.05 ml/min) into a duodenal (n = 11) or mid-intestinal cannula (60 cm from Ligament of Treitz; n = 8), and gastric emptying was measured over the 5-10 min period. Gastric emptying was measured 15 min after IP injection of PYY (1 nmol/rat). PYY antibody (20 mg) or a control antibody (anti-KLH; keyhole limpet hemocyanin) was injected ip 8-12 h before experiments. RESULTS: Exogenous PYY (1 nmol) inhibited gastric emptying and administration of PYY antibody blocked this response. Perfusion of lipid (50 and 100 mg) into the proximal intestine produced a 46% and 66% inhibition of gastric emptying respectively. Inhibition of gastric emptying in response to 50 mg lipid in the proximal small intestine was unaffected by administration of PYY antibody but was abolished by administration of the CCK A receptor antagonist devazepide (0.1 mg/kg ip). Perfusion of lipid into the distal intestine (50 and 100 mg) inhibited gastric emptying by 10% and 32% respectively. Inhibition of gastric emptying in response to 100 mg lipid in the distal intestine was unaffected by PYY antibody. CONCLUSIONS: Lipid perfused into either the proximal or distal intestine inhibits gastric emptying via a PYY-independent mechanism. CCK is involved in proximal lipid induced inhibition of gastric emptying.     

Immunomodulatory function and in vivo properties of Pediococcus pentosaceus OZF, a promising probiotic strain

Some of the important properties of probiotics are the ability to survive during gastrointestinal transit and to modulate the immune functions. The objectives of the reported study were to assess in vivo gastrointestinal survival of orally administered Pediococcus pentosaceus OZF using an animal model BALB/c mice, and to examine its effects on the immune response. Following oral administration to mice, the ability of Pediococcus pentosaceus OZF to pass and survive through the mouse gastrointestinal system was investigated by analyzing the recovery of the strain in fecal samples. Microbiological and polymerase chain reaction (PCR) methods proved that the strain OZF could overcome specific conditions in the gastrointestinal tract of mice and reach the intestine alive after ingestion. To observe the effect of oral administration on immune response, IL-6, IL-12 and IFN-γ were measured by ELISA, and the strain OZF was found to cause increases in IL-6 synthesis in regularly fed mice. However, stimulation was carried out with various concentrations of bacterial ssDNA and heat killed cells of Pediococcus pentosaceus OZF. The heat killed cells of the strain OZF were shown to produce IFN-γ independently from IL-12. On the other hand, a significant difference between control and experimental group was noticed when lipopolysaccharide, a TLR4 (toll like receptor) ligand, was used. Overall, Pediococcus pentosaceus OZF may be a valuable probiotic strain for therapeutic uses. Nevertheless, further studies on the mechanisms of immunomodulatory effect will allow for better clarification of the immune functions of this strain.     

Pharmacokinetics, biological effects, and distribution of (1-->3)-beta-D-glucan in blood and organs in rabbits

The pharmacokinetics, biological effects and distribution in blood and organs of 125I-labeled (1-->3)-beta-D-glucan purified from Candida albicans were analyzed in rabbits during the 24-h period following an intravenous administration.The intravascular half-life of (1-->3)-beta- D-glucan was 1.8 min in the low-dose group (9.3 mug/kg) and 1.4 min in the high-dose group (222 mug/kg), and the mean (+/-SD) total body clearance was 1.12 +/- 0.30 and 1.17 +/- 0.16 ml/min, respectively. The rabbits remained well and (1-->3)-beta-D-glucan failed to alter blood cell counts. Less than 3% of the (125)I-(1-->3)-beta-D-glucan was initially associated with the cellular compartment, and this value decreased further during the 2-h period following administration (P = 0.0001). Over 97% of (125)I-(1-->3)-beta-D-glucan was associated with cell-free plasma, and the majority in plasma appeared to be present in the unbound form (not associated with lipoproteins or plasma proteins). The liver contained more than 80% of the (125)I-(1-->3)-beta-D-glucan detected in the six major organs analyzed.     

Release of distal gut peptide YY (PYY) by fat in proximal gut depends on CCK

We tested the hypothesis that the release of PYY by fat confined to the proximal small intestine is dependent on CCK. Using a multi-fistulated model, plasma PYY levels were compared in 6 dogs after 60 mM oleate was perfused into the proximal one-half of the small intestine following i.v. administration of saline or devazepide, a CCK-A antagonist. Plasma PYY increased with fat (P < 0. 05), but plasma PYY level was lower following devazepide at 60 min and 90 min (P < 0.05). We conclude that CCK serves as a foregut signal linking fat in the proximal gut with the release of distal gut PYY.     

Pharmacokinetics of ipriflavone, an isoflavone derivative, after intravenous and oral administration to rats hepatic and intestinal first-pass effects

Pharmacokinetic parameters of ipriflavone were evaluated after intravenous administration of spray-dried ipriflavone with polyvinylpyrrolidone, SIP (5, 10, 20, and 40 mg/kg as ipriflavone) and oral administration of SIP (50, 100, and 200 mg/kg as ipriflavone) to rats. The hepatic, gastric, and intestinal first-pass effects of ipriflavone were also measured after intravenous, intraportal, intraduodenal, and oral administration of SIP (20 or 50 mg/kg as ipriflavone) to rats. After intravenous and oral administration, the pharmacokinetic parameters of ipriflavone were dose-independent. The extent of absolute oral bioavailability (F) was also independent of oral doses; the mean F value was approximately 24%. Considering the amount of unchanged ipriflavone recovered from 24-hr gastrointestinal tract (the mean value was approximately 12%), the low F values could be due to the hepatic, gastric, and/or intestinal first-pass effects. Based on total body clearance (CL) data of ipriflavone after intravenous administration, the first-pass effect in the heart and lung could be almost negligible, if any, in rats. Approximately 30% of ipriflavone absorbed into the portal vein was eliminated by liver (hepatic first-pass effect) based on intravenous and intraportal administration of SIP. The area under the plasma concentration-time curve from time zero to time infinity (AUC) values after oral administration and intraduodenal instillation of SIP, 50 mg/kg as ipriflavone, were not significantly different, but the values were significantly smaller (129 and 116 microg ml/min) than that after intraportal administration of SIP, 20 mg/kg as ipriflavone (513 microg ml/min based on 50 mg/kg), indicating that gastric first-pass effect of ipriflavone was negligible, but intestinal first-pass effect was considerable in rats. Therefore, the low F value of ipriflavone after oral administration to rats was mainly due to intestinal first-pass effect. The hepatic first-pass effect and incomplete absorption of ipriflavone from rat gastrointestinal tract could also contributed to the low F in rats.     

Expression and immunolocalization of the aquaporin-8 water channel in rat gastrointestinal tract

A remarkable amount, of water is transported in the gastrointestinal (GI) organs to fulfil the secretory and absorptive functions of the GI tract. However, the molecular basis of water movement in the GI epithelial barriers is still poorly known. Important clues about the mechanisms by which water is transported in the GI tract were provided by the recent identification of multiple aquaporin water channels expressed in GI tissues. Here we define the mRNA and protein expression and the cellular and subcellular distribution of aquaporin-8 (AQP8) in the rat GI tract. By semi-quantitative RT-PCR the AQP8 mRNA was detected in duodenum, proximal jejunum, proximal colon, rectum, pancreas and liver and, to a lesser extent, in stomach and distal colon. Immunohistochemistry using affinity-purified antibodies revealed AQP8 staining in the absorptive epithelial cells of duodenum, proximal jejunum, proximal colon and rectum where labeling was largely intracellular and confined to the subapical cytoplasm. Confirming previous results, AQP8 staining was seen at the apical pole of pancreatic acinar cells. Interestingly, both light and immunoelectron microscopy analyses showed AQP8 reactivity in liver where labeling was associated to hepatocyte intracellular vesicles and over the plasma membrane delimiting the bile canaliculi. A complex pattern was observed by immunoblotting with total membranes of the above GI organs incubated with affinity-purified anti-AQP8 antibodies which revealed multiple bands with molecular masses ranging between 28 and 45 kDa. This immunoblotting pattern was not modified after deglycosylation with N-glycosidase F except the 34-kDa band of liver that, as already reported, was partially down-shifted to 28 kDa. No bands were detected after preadsorption of the anti-AQP8 antibodies with the immunizing peptide. The cellular and subcellular distribution of AQP8 suggest physiological roles for this aquaporin in the absorption of water in the intestine and the secretion of bile and pancreatic juice in liver and pancreas, respectively. The large intracellular expression of AQP8 may indicate its recycling between the cytoplasmic compartment and the plasma membrane. The cytoplasmic localization observed may also relate to the involvement of AQP8 in processes of intracellular osmoregulation.     

Early stage-specific immune responses in primary experimental human hookworm infection

To determine the cellular immune response during different stages of hookworm infection, we infected two human volunteers with Necator americanus and followed their immune responses against stage-specific, crude antigen extracts through larval migration, pre-patency, and early patency. After chemotherapy, the volunteers were followed for an additional 6 months. Low-dose N. americanus infection resulted in mild clinical signs and peripheral blood eosinophilia occurred during the estimated time of arrival of juvenile worms in the intestine. After an initial rise in proliferative responses against larval and adult worm antigens, the cellular reactivity decreased until the end of pre-patency, rose again during patency, and dropped after chemotherapy. Before infection and during the course of infection, elevated concentrations of TNF-alpha were detected in supernatants of peripheral blood mononuclear cells (PBMC) stimulated in vitro with third-stage (L3) or adult worm excretory-secretory (ES) antigens, which dropped off after chemotherapy. After stimulation with L3 antigen, elevated concentrations of CCL17 were detected in supernatants during pre-patency and patency. Interestingly, a prominent rise in IL-10 secretion was detected in ES antigen-stimulated PBMC cultures during late pre-patency. During reinfection studies in endemic areas, such distinct cytokine and chemokine profiles might be additional markers to better classify egg-negative patients.     

Comparative expression of hexose transporters (SGLT1, GLUT1, GLUT2 and GLUT5) throughout the mouse gastrointestinal tract

Hexose transporters play a pivotal role in the absorption of food-derived monosaccharides in the gastrointestinal tract. Although a basic knowledge of the hexose transporters has already been gained, their detailed distribution and comparative intensities of expression throughout the gastrointestinal tract have not been fully elucidated. In this study, we quantitatively evaluated the expression of SGLT1, GLUT1, GLUT2, and GLUT5 by in situ hybridization and real-time PCR techniques using a total of 28 segments from the gastrointestinal tract of 9-week-old mice. GLUT2 and GLUT5 mRNA expressions were detected predominantly from the proximal to middle parts of the small intestine, showing identical expression profiles, while SGLT1 mRNA was expressed not only in the small intestine but also in the large intestine. Notably, GLUT1 mRNA was expressed at a considerable level in both the stomach and large intestine but was negligible in the small intestine. Immunohistochemistry demonstrated the polarized localization of hexose transporters in the large intestine: SGLT1 on the luminal surface and GLUT1 on the basal side of epithelial cells. The present study provided more elaborate information concerning the localization of hexose transporters in the small intestine. Furthermore, this study revealed the significant expression of glucose transporters in the large intestine, suggesting the existence of the physiological uptake of glucose in that location in mice.     

Oral glutathione increases tissue glutathione in vivo

Mice were given an oral dose of glutathione (GSH) (100 mg/kg) and concentrations of GSH were measured at 30, 45 and 60 min in blood plasma and after 1 h in liver, kidney, heart, lung, brain, small intestine and skin. In control mice, GSH concentrations in plasma increased from 30 microM to 75 microM within 30 min of oral GSH administration, consistent with a rapid flux of GSH from the intestinal lumen to plasma. Under these GSH-sufficient conditions, no increases over control values were obtained in GSH concentrations in most tissues except lung over the same time course. Mice pretreated for 5 days with the GSH synthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO, 80 mumol/day) had substantially decreased tissue concentrations of GSH. Oral administration of GSH to these GSH-deficient animals gave statistically significant increases in GSH concentrations in kidney, heart, lung, brain, small intestine and skin but not in the liver. Administration of the equivalent amount of the constituent amino acids, glutamate, cysteine, and glycine, resulted in little change in GSH concentrations in all tissues in GSH-deficient animals. Thus, the results show that oral GSH can increase GSH concentrations in several tissues following GSH depletion, such as can occur in toxicological and pathological conditions in which GSH homeostasis is compromised.