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PubMed1991

Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.

Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive drug absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 x 10(-8) to 5 x 10(-5) cm/s. A good correlation was obtained between data on oral absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients greater than 1 x 10(-6) cm/s. Drugs that are absorbed to greater than 1% but less than 100% had permeability coefficients of 0.1-1.0 x 10(-6) cm/s while drugs and peptides that are absorbed to less than 1% had permeability coefficients of less than or equal to 1 x 10(-7) cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal drug absorption.

Adenocarcinoma↗
PubMed1995

Effect of cholephilic dyes on hepatic tight junctional permeability in the rat.

Changes in biliary permeability during cholephilic dye-induced choleresis, as assessed by measuring the movement into bile of two permeability probes, [14C]sucrose and horseradish peroxidase, were analyzed following an i.v. infusion (60 nmol/min per 100 g body wt) of the model cholephilic organic anion sulfobromophthalein in rats. Dye infusion led to a progressive increase of the [14C]sucrose bile-to-plasma ratio, which reached a maximum value after 100 min of dye infusion (+97%). Paracellular entry of horseradish peroxidase, as evaluated by the early peak of its biliary appearance curve, was also selectively increased (+69%), without changes in the later (transcytotic) access of the protein. Additional dose-response studies of biliary permeability to [14C]sucrose, using sulfobromophthalein and rose bengal, showed that this effect was dose-dependent and rapidly reversed by interruption of dye administration. The influence of hydrophobic/hydrophilic balance on this effect was also studied by infusing four dyes covering a broad range of hydrophobicity (phenol red, bromocresol green, sulfobromophthalein, and rose bengal), so as to attain a similar value of dye hepatic content at the end of the experiment (approximately 150 nmol/g liver wt). Under these conditions, a strong positive correlation was found between the increase in biliary permeability to [14C]sucrose and dye hydrophobicity. These results suggest that cholephilic dyes increase tight junctional permeability in a reversible and dose-dependent manner, and that this effect depends on the hydrophobic/hydrophilic balance of the dye.

Animals↗
PubMed1987

Influence of long-term acute heat exposure on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats.

Exposure of conscious young rats to 4 h heat stress at 38 degrees C in B.O.D. incubator was associated with increased blood-brain barrier (BBB) permeability in 14 brain regions studied. In the same regions cerebral flow (CBF) diminished by 4-65%, but the magnitude of flow reduction was not correlated with the degree of increased BBB permeability. On the other hand, a correlation was observed with increased plasma and brain 5-hydroxytryptamine (5-HT) levels. p-Chlorophenylalanine (p-CPA), indomethacin and diazepam pretreatment prevented both the increased BBB permeability and 5-HT levels following heat exposure. Whereas cyproheptadine and vinblastine pretreatment prevented the increased BBB permeability alone. The probable mechanism(s) underlying the BBB permeability is discussed.

Animals↗
PubMed1982

Permeability of bilayers composed of mixtures of saturated phospholipids.

Liposomes composed of an equimolar binary mixture of phospholipids were from a series of saturated phosphatidylcholines (PC) and phosphatidylethanolamines (PE). Mixtures were chosen such that the two phospholipids differed either in terms of head group alone, chain length alone, or both head group and chain length. Cation effluxes, both with and without ionophores (nigericin and valinomycin) were measured over a range of temperatures that encompassed the regions of phase separation for these different lipid mixtures. There was a good correlation between the temperatures at which permeability maxima and phase separation occur. For phospholipid mixtures with the same acyl chain but different head groups (PC vs. PE), the PC component 'controls' permeability. For mixtures of PCs differing in chain length, the short chain lipid dominates the permeability pattern particularly if the chain length are sufficiently different. Lipids differing in both head group and chain length give rise to more complex permeability patterns. The results of the present study are interpreted in terms of a model in which one of the lipid components of the mixture may specifically congregate at defects between co-existing phases and thus 'regulate' permeability.

Liposomes↗
PubMed1994

The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 5-(L)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC50 = 5 x 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreotide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC50 = 1.2 x 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC50 = 3 x 10(-6) mol/l). Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 +/- 3.1% of the area of the glandular stomach. Octreotide reduced the area to 6.4 +/- 1.7% (P < 0.05). The dose-response curve was bell-shaped. 5-(L)-citrullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced microcirculatory stasis and elevated vascular permeability. Ethanol in a concentration of 50% induced an increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150,000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-(L)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of the anaesthetic propofol on the calcium-induced permeability transition of rat heart mitochondria: direct pore inhibition and shift of the gating potential.

Mitochondrial calcium exchanges are involved in intracellular calcium homeostasis and in the contraction-relaxation process in myocytes. The calcium-induced permeability transition of the heart mitochondria inner membrane appears to be an important calcium efflux mechanism involved in some physiological and pathological situations. The negative inotropic effect of the anaesthetic propofol results in part from a decrease in intracellular calcium availability. Thus, this study evaluates the effects of propofol on calcium transport and permeability transition of heart mitochondria. The propofol-inhibition of the permeability transition of liver mitochondria was previously investigated [Eriksson, O. (1991) FEBS Lett. 279, 45-48] in such conditions that its uncoupling effect was not taken into account. We show here that propofol uncoupling results in a decrease in calcium uptake rate which could in part explain the decreased permeability transition rate. However, comparison of equipotent uncoupling concentrations of propofol and carbonylcyanide m-chlorophenylhydrazone reveals that beyond this uncoupling effect, propofol has a direct inhibitory action on the permeability transition pore, concomittant with a shift of its gating potential.

Animals↗
PubMed1986

Xanthine oxidase inhibitors attenuate ischemia-induced vascular permeability changes in the cat intestine.

Previous reports indicate that allopurinol, a xanthine oxidase inhibitor, largely prevents the injury produced by reperfusion of ischemic tissues. In order to further assess the role of xanthine oxidase in ischemia-reperfusion injury, we examined the influence of another inhibitor of the enzyme (pterin aldehyde) on the increased vascular permeability produced by intestinal ischemia. Vascular permeability estimates in autoperfused segments of cat ileum were derived from the relationship between lymph-to-plasma protein concentration ratio and lymph flow. One hour of intestinal ischemia increased vascular permeability to 0.43 +/- 0.02 from a control (nonischemic) value of 0.08 +/- 0.005. In ischemic ileal segments pretreated with purified pterin aldehyde, vascular permeability increased to only 0.15 +/- 0.02. Pretreatment with commercially prepared folic acid, which is contaminated with pterin aldehyde, also attenuated the ischemia-induced increase in vascular permeability (0.16 +/- 0.04). These findings support the hypothesis that xanthine oxidase is a major source of oxygen-free radicals produced during reperfusion of the ischemic small bowel.

Animals↗
PubMed1986

Increased permeability to polyethylene glycol 4000 in rabbits with experimental colitis.

Little information is available regarding colonic permeability to macromolecules in health or disease states. In vivo permeability of rabbit colon to [14C]polyethylene glycol 4000 (14C-PEG) was examined in the presence of immune complex-mediated experimental colitis and compared with that of partially treated (control) and normal rabbits. Permeability was assessed by urinary 14C-PEG excretion after intrarectal administration of 0.1 mM solution of 14C-PEG (1 ml/kg, 7.5 X 10(6) cpm/ml). Experimental colitis greatly increased colonic permeability (p less than 0.001 in two-way analysis of variance) compared with control and normal groups (2.06% +/- 0.19%, 0.14% +/- 0.04%, and 0.01% +/- 0.004%, respectively, of rectally administered counts). Gel diffusion chromatography showed that absorbed 14C-PEG was excreted into urine unchanged, demonstrating its applicability as an inert, nonmetabolizable macromolecular probe. Urinary clearance after mesenteric vein administration of 14C-PEG was similar in normal animals and animals with colitis, implicating colonic absorption as the source of the group differences. Postmortem histology confirmed the acute colitis lesions in the experimental group. These findings support the hypothesis that nonspecific colonic inflammation is associated with significant alterations of mucosal permeability.

Animals↗
PubMed1987

Vasoactive drugs, microvascular permeability, and hemorrhagic pancreatitis in cats.

We investigated the mechanisms by which 16,16-dimethyl prostaglandin E2 and histamine induced pancreatic hemorrhage in an experimental model of acute pancreatitis in cats. In normal animals, when large molecular weight dextran molecules were infused into the systematic circulation, they were recovered in secretin-stimulated pancreatic juice in low concentrations. Both 16,16-dimethyl prostaglandin E2 (in a dose that increased splenic artery blood flow and microvascular permeability) and histamine (in a dose that increased permeability only) increased the amount of dextran recovered in pancreatic juice. Isoproterenol, in a dose that produced the same increase in blood flow as 16,16-dimethyl prostaglandin E2 but which did not increase microvascular permeability, did not alter the amount of dextran recovered. This suggested that the increase in dextran output after 16,16-dimethyl prostaglandin E2 was primarily due to the increase in microvascular permeability caused by the drug. In other experiments, a combination of H1- and H2-receptor antagonists (mepyramine and cimetidine) protected against the development of pancreatic hemorrhage in both the prostaglandin- and histamine-treated animals. Indomethacin (a cyclooxygenase inhibitor) protected against the development of hemorrhage in the histamine-treated animals. Our results support the hypothesis that changes in microvascular permeability may be important in the pathogenesis of parenchymal hemorrhage in this model.

Animals↗
PubMed1992

Glucose and citrate reduce the permeability changes caused by indomethacin in humans.

Nonsteroidal anti-inflammatory drug (NSAID)-induced increased intestinal permeability appears to be a prerequisite for NSAID enteropathy. It has been suggested that early metabolic events leading to the permeability changes may involve inhibition of glycolysis and the tricarboxylic acid cycle, in which case the coadministration of glucose and citrate (the substrates for these metabolic pathways) with indomethacin may afford some protection. The present study, using a combined intestinal absorption-permeability test including 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and [51Cr]ethylene-diaminetetraacetic acid (EDTA) as test probes and the differential urine excretion ratio of [51Cr]-EDTA/L-rhamnose, showed that indomethacin (50 + 75 mg) increased intestinal permeability. A formulation of indomethacin containing 15 mg glucose and 15 mg citrate to each milligram of indomethacin did not increase intestinal permeability significantly above baseline values. When given alone with indomethacin, neither glucose nor citrate (45 mg to each milligram of indomethacin) had any protective effects. Pharmokinetic studies showed that the effects of glucose and citrate cannot be explained on the basis of altered drug absorption. These results suggest a new approach to reducing the small intestinal side effects of NSAIDs.

Adult↗
PubMed1993

Sucrose: a novel permeability marker for gastroduodenal disease.

BACKGROUND: Nonsteroidal anti-inflammatory agents (NSAIDs) commonly cause asymptomatic gastroduodenal damage that may be clinically severe. At present the only method to determine the presence or absence of such damage is by invasive techniques such as endoscopy. Because distal small intestinal damage can be noninvasively detected with oral permeability tests, the hypothesis that gastroduodenal damage could be detected using similar methods was examined in the present study. RESULTS: Animal data are presented suggesting that sucrose represents an ideal probe molecule to detect increased gastroduodenal permeability in a site-specific manner. With gastroduodenal damage, caused by either ethanol or NSAIDs, sucrose permeability is increased. Furthermore, because sucrose is rapidly degraded within the small intestine, this probe does not detect small intestinal damage, making it specific for the upper gastrointestinal tract. Finally, a pilot study in humans is presented to show the use of this technique in evaluating human gastric permeability. CONCLUSIONS: Sucrose represents a novel permeability probe with specificity for damage of the upper gastrointestinal tract. In animals and humans it appears useful to noninvasively detect gastroduodenal injury caused by several agents.

Animals↗
PubMed1995

Effect of changing intestinal flow rate on a measurement of intestinal permeability.

BACKGROUND/AIMS: The flow rate of fluid through the proximal small intestine varies widely under normal physiological conditions. The aim of this study was to assess the effect of changes in flow rate on the passive permeability of the aqueous paracellular pathway of the human jejunum. METHODS: Normal subjects were studied in vivo during constant perfusion of 30-cm loops of jejunum at flow rates of 5, 10, or 20 mL/min. The permeability ratio of L-xylose/urea was used to assess apparent permeability of the mucosa and to calculate the average pore radius of the aqueous pathway for passive diffusion. RESULTS: Increasing jejunal flow rate from 5 to 20 mL/min significantly decreased the L-xylose/urea permeability ratio from 0.35 to 0.23 and decreased average calculated pore radius of the diffusion pathway from 13 A to 8 A. CONCLUSIONS: Increases in flow rate in the normal physiological range decrease the estimated pore size of normal healthy jejunal mucosa. Because increasing flow rate is known to increase exposure of luminal fluid to the intervillus space, the results of this study are best explained by postulating that cells lining the sides of villi are less permeable than cells lining the villus tips.

Adult↗
PubMed1995

FK506 increases permeability in rat intestine by inhibiting mitochondrial function.

BACKGROUND & AIMS: Under normal physiological conditions, the intestine presents an adenosine triphosphate (ATP)-dependent barrier to luminal contents. Disruption of this barrier function can occur when cellular metabolism is compromised. This study examined the effects of FK506 on intestinal permeability and enterocyte metabolic function in Lewis rats. METHODS: Rats were administered FK506 at a dose of 0.1, 0.5, or 2 mg/kg on alternate days for 6 weeks. Intestinal permeability was assessed by measuring urinary recovery of 99mTc-diethylenetriamine pentacetate, and electrophysiological conductance measurements were performed in Ussing chambers. Metabolic function was assessed in isolated enterocytes by measuring total ATP and CO2 release from [14C]pyruvate and [14C]glucose. RESULTS: Rats treated with FK506 showed a dose-dependent reduction in weight gain as well as increased in vivo and in vitro intestinal permeability. There was no difference in plasma creatinine or urinary output. Changes in permeability correlated with reduced ATP levels and CO2 release because of diminished mitochondrial function. Lactate production, as a measure of glycolytic activity, was not altered by FK506. CONCLUSIONS: In a dose-dependent manner, FK506 treatment in rats reduces weight gain, increases intestinal permeability, and decreases the ability of the small intestine to use glucose as an energy source.

Adenosine Triphosphate↗
PubMed1984

The role of membrane bound glycoprotein on the permeability of liposomes.

The liposome permeability to potassium and methanosulfonate ions was determined in the presence of bound glycoprotein and protein. The permeability changes were registered by light-scattering measurements of the osmotic volume changes of liposome suspension after mixing with solutions containing K+ and MS- ions respectively. The permeability changes varied considerably with the change of glycoprotein-protein molar ratio in the liposomes. It was suggested that topological distribution of both molecules (glycoprotein and protein) in the lipid bilayer would play a substantial role and influence the permeability. It was confirmed from fluorescence measurements with ANS as a fluorescence marker. There was an increase of the number of binding sites (n) for ANS, increasing glycoprotein-protein molar ratio in the liposomes. These results were interpreted in terms of electrostatical changes of the membrane lipid region and membrane surface, caused by the interaction of glycoprotein and protein with lipids, as well as the associated role of these components on the permeability.

Acetylcholinesterase↗
PubMed1993

Mucosal permeability to 51Cr EDTA following subclinical intestinal ischemia-reperfusion injury in the weanling rat.

The etiology of necrotizing enterocolitis (NEC) is uncertain. We have hypothesized that subclinical intestinal ischemia might result in increased mucosal permeability to intraluminal toxins or bacteria, resulting in inflammation and NEC. In order to pursue this hypothesis, we designed a series of studies to investigate whether the first assumption is correct, ie whether a subclinical ischemia-reperfusion injury (IRI) results in increased mucosal permeability. Using a model of superior mesenteric artery occlusion (SMAO) in weanling rats, we initially defined 10-minute SMAO as "subclinical" IRI (ie, 100% survival, no histological changes, and no hemodynamic instability). Mucosal permeability to a standard probe molecule (51Cr EDTA) was then measured after sham operation, or 2-minute or 10-minute SMAO. There was an early increase in permeability 30 minutes after reperfusion in the 10-minute SMAO group, which was completely reversed by 2 hours. Further studies suggested that having passed through the mucosa, the probe entered the systemic circulation via both portal venous and intestinal lymphatic routes. Subclinical intestinal IRI results in an early, reversible increase in mucosal permeability to 51Cr EDTA, which may be important in the pathogenesis of NEC. Further studies are required to fully characterize this phenomenon, and to determine the mechanisms by which it occurs.

Animals↗
PubMed1988

Effect of chronic partial pancreatic duct obstruction on pancreatic duct secretory pressure and permeability in cats.

Pancreatic secretion during pancreatic duct obstruction results in increased duct pressure. The normally impermeable pancreatic duct becomes permeable to macromolecules the size of pancreatic enzymes after secretion against obstruction. Permeability and morphologic changes may be related to increased secretory pressure during obstruction. We obstructed the main pancreatic duct of cats by 25-100% of its luminal diameter in different groups for 2, 7, or 28 days. Permeability to macromolecules of fluoresceinated dextran (FD) was greatest in cats with less than 75% obstruction compared with cats with greater than 75% obstruction regardless of the duration of obstruction. The frequency of permeability to FD decreased significantly as both the degree and duration of obstruction increased. Secretory pressure also changed according to degree and duration of obstruction. The highest pressures were in cats with complete obstruction at 2 days. Pressure decreased as the degree and duration of obstruction increased. Histologic changes such as acinar lobular atrophy and interstitial fibrosis were most severe in cats with the greatest degree and duration of obstruction. Pressure and permeability changes indicate a greater sensitivity to increased duct pressure than previously thought. These observations may clarify the role of pancreatic duct obstruction in pancreatic disease.

Animals↗
PubMed1986

Influence of long-term immobilization stress on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats.

Eight hours immobilization stress in young rats has increased the blood-brain barrier (BBB) permeability in 12 out of 14 brain regions studied. In the same regions cerebral blood flow (CBF) diminished by 2-37%, but the magnitude of flow reduction was not correlated with the degree of increased BBB permeability. On the other hand, a correlation was observed with increased plasma and brain 5-HT levels. The increased BBB permeability and increased 5-HT levels were prevented by pretreatment with p-CPA, indomethacin and diazepam. Cyproheptadine and vinblastine pretreatment prevented the occurrence of increased BBB permeability alone. The probable mechanism(s) underlying the breakdown of BBB permeability is discussed.

Animals↗
PubMed1993

Blood-brain barrier permeability and the brain extracellular space in acute cerebral inflammation.

The diffusion properties of the brain cortical extracellular space have never been examined in models of inflammation, even though inflammation can cause increased blood-brain barrier permeability. Uptake of intravascular 125I-labelled albumin and the diffusion of the tetramethylammonium ion within the brain extracellular space was measured in an experimental brain abscess to determine the effect of acute inflammation upon blood-brain barrier permeability and diffusion properties of the cortical extracellular space. The blood-brain transfer constant for albumin was increased in the abscess region, indicating that an increase in blood-brain barrier permeability occurred in animals inoculated with a weakly pathogenic strain of Staphylococcus aureus. The volume fraction of the extracellular space, as measured by the diffusion of tetramethylammonium ion, ranged from 0.19 to 0.23 in bacteria inoculated subjects and from 0.21 to 0.22 in controls. The tortuosity of the extracellular space ranged from 1.40 to 1.42 in bacteria inoculated subjects and was 1.39 in controls. These results showed that the volume fraction and tortuosity of the cortical extracellular space were not affected by inflammation even though vascular permeability was increased. This result was supported by the finding that brain water content, measured in the same animals, was increased to a non-significant extent in the bacteria inoculated subjects. These findings lead to the conclusion that acute inflammation induced by a weak pathogen can cause increased blood-brain barrier permeability without a significant change in the diffusion properties of the brain cortical space.

Animals↗