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PubMed2004

Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis.

Cyclophilin-D is a peptidylprolyl cis-trans isomerase of the mitochondrial matrix. It is involved in mitochondrial permeability transition, in which the adenine nucleotide translocase of the inner membrane is transformed from an antiporter to a non-selective pore. The permeability transition has been widely considered as a mechanism in both apoptosis and necrosis. The present study examines the effects of cyclophilin-D on the permeability transition and lethal cell injury, using a neuronal (B50) cell line stably overexpressing cyclophilin-D in mitochondria. Cyclophilin-D overexpression rendered isolated mitochondria far more susceptible to the permeability transition induced by Ca2+ and oxidative stress. Similarly, cyclophilin-D overexpression brought forward the onset of the permeability transition in intact cells subjected to oxidative stress. In addition, in the absence of stress, the mitochondria of cells overexpressing cyclophilin-D maintained a lower inner-membrane potential than those of normal cells. All these effects of cyclophilin-D overexpression were abolished by cyclosporin A. It is concluded that cyclophilin-D promotes the permeability transition in B50 cells. However, cyclophilin-D overexpression had opposite effects on apoptosis and necrosis; whereas NO-induced necrosis was promoted, NO- and staurosporine-induced apoptosis were inhibited. These findings indicate that the permeability transition leads to cell necrosis, but argue against its involvement in apoptosis.

Amino Acid Sequence↗
PubMed2002

Evidence against aquaporin-1-dependent CO2 permeability in lung and kidney.

AQP1-dependent CO2 transport has been suggested from the increased CO2 permeability in Xenopus oocytes expressing AQP1. Potential implications of this finding include AQP1-facilitated CO2 exchange in mammalian lung and HCO3-/CO2 transport in kidney proximal tubule. We reported previously that: (a) CO2 permeability in erythrocytes was not affected by AQP1 deletion, (b) CO2 permeability in liposomes was not affected by AQP1 reconstitution despite a 100-fold increased water permeability, and (c) CO2 blow-off by the lung in living mice was not impaired by AQP1 deletion. We extend these observations by direct measurement of CO2 permeabilities in lung and kidney. CO2 transport across the air-space-capillary barrier in isolated perfused lungs was measured from changes in air-space fluid pH in response to addition/removal of HCO3-/CO2 from the pulmonary artery perfusate. The pH was measured by pleural surface fluorescence of a pH indicator (BCECF-dextran) in the air-space fluid. Air-space fluid pH equilibrated rapidly (t(1/2) approximately 6 s) in response to addition/removal of HCO3-/CO2. However, the kinetics of pH change was not different in lungs of mice lacking AQP1, AQP5 or AQP1/AQP5 together, despite an up to 30-fold reduction in water permeability. CO2 transport across BCECF-loaded apical membrane vesicles from kidney proximal tubule was measured from the kinetics of intravesicular acidification in response to rapid mixing with a HCO3-/CO2 solution. Vesicles rapidly acidified (t(1/2) approximately 10 ms) in response to HCO3-/CO2 addition. However the acidification rate was not different in kidney vesicles from AQP1-null mice despite a 20-fold reduction in water permeability. The results provide direct evidence against physiologically significant transport of CO2 by AQP1 in mammalian lung and kidney.

Algorithms↗
PubMed2002

Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.

Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values <150 nm/s compared with the non-CNS set (13 of 45, 28.9%). The majority of drugs (72.0%, 67 of 93) were not Pgp substrates; however, 49.5% (46 of 93) were positive in the calcein-AM assay when tested at 100 microM. The CNS drug set (n = 7 of 48, 14.6%) had a 3-fold lower incidence of Pgp-mediated efflux than the non-CNS drug set (n = 19 of 45, 42.2%). Analysis of 18 physicochemical properties revealed that the CNS drug set had fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area, and reduced flexibility compared with the non-CNS group (p < 0.05), properties that enhance membrane permeability. This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs. For CNS delivery, a drug should ideally have an in vitro passive permeability >150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Atriopeptin-induced increases in endothelial cell permeability are associated with elevated cGMP levels.

To investigate the mechanism of nonrenal capillary hyperfiltration, we studied the effect of atriopeptin (AP) III and AP I on permeability and intracellular cyclic nucleotide levels in cultured bovine pulmonary artery endothelial cell monolayers. Permeability to albumin was assessed by the albumin transfer rate across endothelial cell monolayers, following a 4-h incubation with atriopeptins. AP III (0.01, 0.1, and 1 microM) caused a concentration-dependent increase in the albumin transfer rate. AP III induced a threefold increase in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels during the incubation period. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), enhanced the AP III-induced increase in permeability and cGMP accumulation by 16-fold at maximum. 8-Bromoguanosine 3',5'-cyclic monophosphate, a hydrolysis-resistant cGMP analogue, caused a slight but significant increase in permeability. In contrast, AP I, a weak agonist of the cGMP-coupled ANP receptor, did not elicit an increase in permeability at concentrations of 0.1 and 1 microM. Although AP I (1 microM) caused a significant increase in cGMP by 33 and 60% in the absence and presence of IBMX, the increase was markedly less compared with AP III. AP III did not cause a change in intracellular cAMP levels during the incubation period. These observations suggest that in our system AP III increases the permeability of endothelial cell monolayers in association with an elevated cGMP level. Thus an increase in permeability might be involved in the mechanism of ANP-induced capillary hyperfiltration.

Animals↗
PubMed1986

The effects of calcium hydroxide on dentin permeability.

Calcium hydroxide paste was applied to human dentin in vitro to determine its effects on dentin permeability. Discs of dentin were acid-etched on both sides to permit determination of their maximum permeability. Smear layers were then applied to the enamel sides of the discs, thereby reducing dentin permeability 99%. Topical application of Ca(OH)2 paste to the smear layer reduced dentin permeability further, to levels 48% below that of untreated smear layers. When the Ca(OH)2-treated smear layers were exposed to 6% citric acid for two min, dentin permeability returned to the initial acid-etched value, demonstrating that Ca(OH)2 offers little protection to acid challenge. Treatment of acid-etched dentin with Ca(OH)2 produced a similar reduction in dentin permeability, which was restored to normal following acid challenge. Thus, Ca(OH)2 is effective at reducing the permeability of both the smear layer and of acid-etched dentin, in vitro.

Acid Etching, Dental↗
PubMed1975

Permeability changes in the blood-brain barrier: causes and consequences.

1. Generalized changes in blood-brain barrier (BBB) permeability are accompanied by extravasation of plasma proteins; thus, they are readily studied with protein markers or protein-dye complexes. Selective changes in permeability involve alterations in BBB transport systems; they are best studied with techniques which detect the qualitative hallmarks of carrier-mediated transport, namely saturation, competition, and stereospecificity. 2. Quantitative assessments of the selective permeability of the BBB can be made from the saturation data expressed in terms of Michaelis-Menten kinetics. The advantages of the latter are twofold: (a) alterations elicited by modified barrier affinity (Km) can be distinguished from alterations in carrier capacity (Vmax); (b) the relative rates of flux of a metabolite across the BBB can be placed in the perspective of cerebral metabolism. Kinetic data on transport processes in the BBB are obtained by either constant infusion or single injection techniques. Results obtained with both methodologies have been comparable. 3. Independent transport systems for glucose, neutral amino acids, basic amino acids, and monocarboxylic acids have been identified in the BBB. The description of these transport systems in kinetic terms provides a background of information on intact mechanisms to which altered transport can be compared. 4. Experimental evidence indicates that the availability of key metabolic substrates, such as glucose or essential amino acids, may be rate-limiting in cerebral metabolism. A working hypothesis was developed that the consequences of a selective change in barrier permeability to one or more of these essential substrates are directly related to altered rates of reaction in substrate-limited pathways, e.g., cerebral protein or neuro-transmitter biosynthesis. 5. Toxicological causes of generalized changes in BBB permeability include hypertonic solutions, organic solvents, surface-active agents, enzymes, and heavy metals. Some agents, e.g., mercury or hypertonic urea, induce selective changes in BBB transport at doses much lower than those required for nonspecific barrier break-down. Subtle changes in transport of metabolic substrates may remain unrecognized unless specifically investigated, yet may have profound consequences on brain metabolism. 6. Pathological processes can also induce selective changes in BBB permeability. Such changes often temporally precede the more generalized alterations in permeability that can occur during pathogenesis. For example, in brain edema due to an ischemic infarct, glucose transport increases during the early cytotoxic phase, whereas generalized changes are not detected until the later vasogenic phase.

Amines↗
PubMed2003

Augmentation of endothelial cell monolayer permeability by hyperthermia but not tumor necrosis factor: evidence for disruption of vascular integrity via VE-cadherin down-regulation.

Following isolated limb perfusion (ILP) with hyperthermia (H T), TNF and melphalan, there is immediate tumor softening secondary to augmentation of capillary leak in the tumor neovasculature. TNF can induce vascular permeability but is always used with HT during ILP and the contribution of the latter on permeability is not known. This study characterizes the effects of HT and TNF on vascular permeability in vitro. Permeability across confluent human umbilical vein endothelial cells exposed to HT (40 degrees C) with or without 0.1-1000 ng/ml TNF was assessed by quantitating flux of albumin bound Evan's Blue dye from the upper to lower chamber. Immunofluorescent staining for VE-cadherin and F-actin was performed after human umbilical vein endothelial cells (hUVECs) were exposed to these conditions. HT induced a significant and reversible increase in permeability compared to untreated hUVECs (p<0.001) whereas barrier function was not altered by TNF. Untreated hUVECs had uniform cell surface staining for VE-cadherin, the primary endothelial intercellular adhesion molecule, with colocalization of F-actin cytoskeletal elements. HT resulted in a marked decrease in VE-cadherin staining and contraction of F-actin at sites of endothelial cell-cell separation. These data demonstrate that under conditions relevant to those used in ILP, HT but not TNF contributes to a rapid and reversible change in endothelial cell permeability in association with a down regulation of VE-cadherin. These data support the use of HT in isolation perfusion and demonstrate a novel mechanism for alterations in microvascular permeability by HT.

Actins↗
PubMed1993

Differential response of the permeability of the rat liver canalicular membrane to sucrose and mannitol following in vivo acute single and multiple exposures to microwave radiation (2.45 GHz) and radiant-energy thermal stress.

Both acute and chronic exposures to microwave radiation altered the function of the rat canalicular membrane. A single acute exposure to microwave radiation [80 mW/cm2, 2.45 GHz, continuous wave, 30 min exposure (SAR approximately equal to 72 W/kg)] or a matched radiant-energy thermal load, both designed to raise core body temperature approximately 3 degrees C, decreased the permeability of the canalicular membrane of male Sprague-Dawley rats to sucrose. The change in canalicular membrane permeability was demonstrated by a significant increase in the percentage of [3H]sucrose recovered in bile following its administration by a segmented retrograde intrabiliary injection. Similar acute exposures to microwave and radiant-energy thermal sources produced no significant alterations in canalicular membrane permeability to [14C]mannitol. In both acute exposure protocols, a rapidly reversible increase in bile flow rate was observed. Four exposures (30 min/day x 4 days) to either microwave radiation (80 mW/cm2) or a matched radiant-energy thermal load resulted in a significant depression in bile flow rate at normothermic temperatures. Animals receiving multiple exposures to microwave radiation had significant decreases in canalicular membrane permeability to both [3H]sucrose and [14C]mannitol, while similar exposure to radiant-energy thermal load alone altered canalicular membrane permeability to [3H]sucrose. An examination of the hepatic clearance of sucrose and mannitol following acute microwave exposure demonstrated no significant differences. Thus acute single exposure to microwave and radiant-energy thermal loads produced similar alterations in canalicular membrane permeability. Conversely, multiple exposures produced nonreversible changes in bile flow rate and canalicular membrane permeability, with microwave exposure producing greater alterations in the function of the canalicular membrane than an equivalent radiant-energy thermal load.

Animals↗
PubMed1996

Vascular permeability in the peripheral autonomic and somatic nervous systems: controversial aspects and comparisons with the blood-brain barrier.

Endothelium, choroidal epithelium, and arachnoid exclude plasma proteins from most parts of the mammalian central nervous system (CNS). Nerve roots, in contrast, have permeable capillaries and permeable pia-arachnoid sheaths. Diffusion of plasma proteins into the cerebrospinal fluid is probably prevented by slow bulk flow along a pressure gradient from the subarachnoid space into the veins of the roots. In nerves, the perineurium prevents diffusion of proteins from the epineurium into the endoneurium. Capillaries within fascicles are permeable to macromolecules, though less so than the microvessels of roots and ganglia. Endoneurial vascular permeability is lowest in rats and mice, but even in these species albumin is normally present in the extracellular spaces around the nerve fibers. The so-called blood-nerve barrier is not equivalent to the blood-brain barrier. Capillaries in sensory and sympathetic ganglia are fully permeable to macromolecules, and extravasated protein is in contact with neuronal cell bodies and neurites. An impenetrable perineurium surrounds each ganglion, but serves no obvious purpose when the vessels inside are as permeable as those outside. The enteric nervous system lacks a perineurium, and the neurons in its avascular ganglia and tracts are exposed to extracellular fluid formed by permeable vessels in adjacent tissues of the gut. The reasons for excluding macromolecules from some parts of the nervous system are obscure. Carrier-mediated transport, which maintains a constant supply of ions, glucose, and other metabolites to cells in the CNS, would be impossible if larger molecules could diffuse freely. Presumably the metabolic needs of ganglia are adequately met by exchange vessels similar to those of nonnervous tissues. Most of the CNS is protected from exogenous toxic substances that bind to plasma proteins. Peripheral neurons and glial cells are damaged by some such substances because of the lack of blood-tissue barriers.

Animals↗
PubMed1998

A review of experimental measurements of effective diffusive permeabilities and effective diffusion coefficients in biofilms.

Experimental measurements of effective diffusive permeabilities and effective diffusion coefficients in biofilms are reviewed. Effective diffusive permeabilities, the parameter appropriate to the analysis of reaction-diffusion interactions, depend on solute type and biofilm density. Three categories of solute physical chemistry with distinct diffusive properties were distinguished by the present analysis. In order of descending mean relative effective diffusive permeability (De/Daq) these were inorganic anions or cations (0.56), nonpolar solutes with molecular weights of 44 or less (0.43), and organic solutes of molecular weight greater than 44 (0.29). Effective diffusive permeabilities decrease sharply with increasing biomass volume fraction suggesting a serial resistance model of diffusion in biofilms as proposed by Hinson and Kocher (1996). A conceptual model of biofilm structure is proposed in which each cell is surrounded by a restricted permeability envelope. Effective diffusion coefficients, which are appropriate to the analysis of transient penetration of nonreactive solutes, are generally similar to effective diffusive permeabilities in biofilms of similar composition. In three studies that examine diffusion of very large molecular weight solutes (>5000) in biofilms, the average ratio of the relative effective diffusion coefficient of the large solute to the relative effective diffusion coefficient of either sucrose or fluorescein was 0.64, 0.61, and 0.36. It is proposed that large solutes are effectively excluded from microbial cells, that small solutes partition into and diffuse within cells, and that ionic solutes are excluded from cells but exhibit increased diffusive permeability (but decreased effective diffusion coefficients) due to sorption to the biofilm matrix.

Biofilms↗
PubMed1997

Influence of ePTFE polymer implant permeability on the rate and density of corneal extracellular matrix synthesis.

Microporous polymers have great potential for the production of corneal keratoprosthetic devices. Keratocytes invade the pores of expanded polytetrafluoroethylene implants (ePTFE) and collagen synthesis occurs. This ePTFE becomes translucent after its implantation in the stroma of rabbit cornea. The rate and density of cell growth within this polymer depends on the implant thickness, pore size, and its placement in the cornea. We have investigated the influence of the polymer permeability on the collagen and protein contents ePTFE implants. Rabbit corneal stroma were implanted with ePTFE disks (6 mm in diameter) by intralamellar keratoplasty. The implanted polymers were removed from the stroma after 3 to 6 months. The collagen and protein contents were determined after pepsin solubilization. The collagen content of the high-permeability implant was 3.7-fold greater than that of the low-permeability implant 3 months after implantation and 2.4-fold greater after 6 months. The total protein content of the high-permeability implant was 2.5-fold greater than that of low-permeability implant at 3 months and was the same after 6 months. The collagen-to-protein ratio was 68% in the high-permeability implants, and thus similar to that of normal corneal stroma. Thus, high polymer permeability increased both the rate and density of the corneal extracellular matrix ingrowth.

Animals↗
PubMed1997

Bradykinin- and thrombin-induced increases in endothelial permeability occur independently of phospholipase C but require protein kinase C activation.

We determined whether activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and a subsequent increase in cytosolic calcium concentration ([Ca2+]i) was an obligatory signaling event mediating the increase in transendothelial permeability induced by bradykinin (BK) and alpha-thrombin (alpha-T). Both BK and alpha-T (each at a concentration range of 0.01-1 microM) caused dose-dependent increases in transendothelial 125I-albumin permeability in cultured bovine pulmonary artery endothelial cell monolayers. Both agonists also produced a rise in inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] by 10 sec that was followed by a prolonged increase in [Ca2+]i. Pretreatment of endothelial cells with the PLC inhibitor, 1-(6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dion [(U73122) at 10 microM for 15 min], prevented the increases in Ins(1,4,5)P3 and [Ca2+]i induced by both BK and alpha-T. However, inhibition of PLC with U73122 or another PLC inhibitor, neomycin, did not prevent the increase in endothelial permeability induced by either agonist. In contrast, depletion of cellular protein kinase C (PKC) with phorbol-12-myristate 13-acetate (0.01 microM for 20 hr) increased both BK- and alpha-T-induced phosphoinositide turnover but inhibited the agonist-induced increase in permeability. A PKC inhibitor, staurosporine (5 microM) likewise inhibited the BK-induced increase in endothelial cell permeability to albumin. We conclude that increases in endothelial permeability induced by the inflammatory mediators, BK and thrombin, can occur independently of PLC activation and increased [Ca2+]i but that a PKC-dependent pathway is required for the permeability response.

Animals↗
PubMed1993

The structural barrier of absorptive mucosae: site difference of the permeability of fluorescein isothiocyanate-labelled dextran in rabbits.

The permeability of fluorescein isothiocyanate-labelled dextran (FD, M.W. 4400-71,200) across nasal, buccal, duodenal, jejunal, ileal, colonic, and rectal mucosae excised from rabbits has been measured to estimate the structural barrier of absorptive mucosae using Ussing-type diffusion chambers. The permeability coefficient of FD in all these mucosae decreased with increasing molecular weight. The rank order of FD permeability did not always correlate with the electrical resistance of the mucosae. Among components of the small intestine (duodenum, jejunum, ileum) and the large intestine (colon, rectum), however, the rank order of FD permeability corresponded to the magnitude of the electrical resistance in each instance; the upper colonic mucosa showed the highest permeability, especially in FD of low molecular weight, and permeability of the rectal mucosa was lowest except for the duodenal mucosa. The nasal mucosa showed the lowest electrical resistance and the highest permeability of those studied, suggesting that it has a leaky structural barrier.

Animals↗
PubMed1992

Endothelium-derived relaxing factor contributes to the regulation of endothelial permeability.

To determine whether endothelium-derived relaxing factor (EDRF) contributes to the regulation of endothelial permeability, the transendothelial flux of 14C-sucrose, a marker for the paracellular pathway across endothelial monolayers (Oliver, J. Cell. Physiol. 145:536-548, 1990), was examined in monolayers of bovine aortic endothelial cells grown on collagen-coated filters. The permeability coefficient of 14C-sucrose was significantly decreased by 10(-3) M 8-Bromoguanosine 3',5'-cyclic monophosphate or by 5 x 10(-6) M glyceryl trinitrate, an activator of soluble guanylate cyclase. Depletion of L-arginine from endothelial monolayers increased 14C-sucrose permeability from 3.21 +/- 0.59 to 3.88 +/- 0.50 x 10(-5) cm.sec-1 (mean +/- SEM; n = 6; P < 0.05). The acute administration of 5 x 10(-4) M L-arginine to monolayers depleted of this amino acid decreased 14C-sucrose permeability from 2.91 +/- 0.27 to 2.52 +/- 0.26 x 10(-5) cm.sec-1 (n = 11; P < 0.05). 14C-sucrose permeability was increased by 10(-7) M bradykinin and this effect was enhanced by the presence of each one of the following compounds: 10(-5) M methylene blue, 4 x 10(-6) M oxyhemoglobin, 5 x 10(-4) M NG-methyl-L-arginine or 5 x 10(-4) M N omega-nitro-L-arginine. These results suggest that EDRF contributes to the sealing of the endothelial monolayer and that EDRF released by bradykinin acts as a feedback inhibitor attenuating the increase in endothelial permeability induced by this peptide. Because endothelial cells have the ability to contract and relax and possess guanylate cyclase responsive to nitric oxide, our results suggest that EDRF decreases 14C-sucrose permeability by relaxing endothelial cells, thereby narrowing the width of endothelial junctions.

Animals↗
PubMedDate not supplied

Dependence of apparent diffusion coefficients on axonal spacing, membrane permeability, and diffusion time in spinal cord white matter.

We used a numerical simulation of water self-diffusion among permeable cylinders to predict the dependence of MR-based apparent diffusion coefficients in white matter on axonal separation, barrier permeability, and diffusion time (T). The transverse apparent diffusion coefficient (tADC), calculated with simulated diffusion-sensitizing gradients perpendicular to the axon fibers, remains a function of T down to diffusion times as short as .1 microsec for a range of diffusion barrier permeability. As the diffusion time lengthens, the response of tADC depends on axon diameter, with decreases in tADC occurring earliest, and most dramatically, for the smallest fiber diameter simulated (2 microm). For a given axonal separation, asymptotic values of ADC are determined by permeability alone and are the same for 2-microm and 11-microm fibers of equal membrane permeability. The effect of increased relative intracellular volume is manifested primarily in a decrease in tADC at short T. Increases in interaxonal spacing increase the tADC at asymptotically long diffusion times and reduce the dependence on permeability. However, at the widest plausible axonal separations, permeability remains an important determinant of tADC. These simulations may enhance interpretation of measured tADC in the context of the underlying physiologic and structural changes at the cellular level that accompany white-matter disease.

Animals↗
PubMed2002

Prediction of steady-state skin permeabilities of polar and nonpolar permeants across excised pig skin based on measurements of transient diffusion: characterization of hydration effects on the skin porous pathway.

The applicability of a two-parameter Fickian diffusion model for predicting the skin steady-state permeability based on measurements of the transient transport of permeants across the skin was tested. Using five model permeants possessing different physicochemical properties and pig skin as the model membrane, the skin permeabilities predicted by the two-parameter Fickian diffusion model were compared with the measured skin permeabilities. Results show that the transient skin permeation profiles of the hydrophobic permeants, estradiol, testosterone, and dolichol, across split-thickness pig skin can be modeled adequately by the two-parameter Fickian diffusion model (with constant parameter values), and therefore, that this model can be utilized to shorten the experimental time required to determine the skin permeabilities of these compounds. However, the skin permeabilities of the highly hydrophilic permeants, mannitol and sucrose, predicted by the two-parameter Fickian diffusion model (with constant parameter values) were significantly lower than the experimentally determined values, indicating that the dominant skin pathway of polar permeants within the excised pig skin undergoes significant structural changes during the in vitro diffusion cell studies. Although the skin permeability values determined experimentally using the traditional steady-state method normally correspond to a highly hydrated skin sample, the two-parameter Fickian diffusion model enables an estimation of the skin permeability of the skin membrane at its less-hydrated state (a condition more representative of in vivo and clinical situations). Using the two-parameter Fickian diffusion model and a recently developed skin porous-pathway theory, the effects of skin hydration on the skin porous pathway within the excised pig skin were characterized. Specifically, we found that hydration leads to induction of new pores/reduction of the tortuosity of existing pores within the excised pig skin during the 48 h diffusion cell studies conducted, while the skin average pore radii remain relatively constant (approximately 26 A) for up to 48 h.

Algorithms↗
PubMed2004

Frog intestinal sac: a new in vitro method for the assessment of intestinal permeability.

The aim of this study was to evaluate a new experimental protocol utilizing isolated frog intestinal sacs for the assessment of intestinal drug permeability in humans. Segments of approximately 5.0 cm in length were used for these experiments. The intestinal sacs were filled with a solution of the appropriate drug in frog Ringer (FR) and immersed in a vial containing fresh FR. The transport was monitored for a period ranging from 2 to 5 h by moving the intestinal sac at each time point to a new vial containing fresh medium (Method A). Alternatively, according to Method B, at predetermined times aliquots of receiving mixture were taken up without removing the intestinal sac, and replaced with fresh drug-free FR. In all cases, the samples were analyzed by HPLC. A series of 20 noncongeneric drugs, predominantly absorbed by passive diffusion mechanism, was examined. The results indicate that drugs completely absorbed in humans had Papp values greater than 1 x 10(-6) cm/s, while drugs absorbed <90% had Papp values lower than 1 x 10(-6) cm/s. By plotting Log Papp values against percent human absorption, an approximately sigmoidal relationship was obtained. The frog intestinal sac method was evaluated as a permeability model to classify the 20 studied drugs into the Biopharmaceutics Classification System (BCS). By comparing the predictions made by this new approach with those reported in literature, it can be concluded that a satisfactory biopharmaceutical classification may be based on the Papp values determined by the frog intestinal permeability. Molecular properties relevant to passive intestinal permeability were considered to evaluate the correlation with the frog intestinal permeability rates recorded. Good relationships were observed when hydrogen-bonding parameters were expressed as a function of the Log Papp values. It can be concluded that the in vitro permeability coefficient deduced from isolated frog intestinal experiments can be used for predicting peroral absorption in humans for passively absorbed compounds. Computational methods for prediction of frog intestinal permeability may be applied in a highly simplified manner.

Animals↗
PubMed2006

A multiphase microscopic diffusion model for stratum corneum permeability. I. Formulation, solution, and illustrative results for representative compounds.

A two-dimensional microscopic transport model of the stratum corneum (SC) incorporating corneocytes of varying hydration and permeability embedded in an anisotropic lipid matrix is presented. Results are expressed in terms of a dimensionless permeability (P(SC/w)(comp), which is a function of two dimensionless parameters, R and sigma. R is a ratio of transbilayer to lateral molecular flows within a lipid bilayer and sigma is the ratio of (lateral) permeability in the lipid phase, D(lip)K(lip/w), to that in the corneocyte phase, D(cor)K(cor/w.) The shape of the dimensionless permeability surface is also governed by the arrangement of the SC lipids, where Model 1 represents the extreme in which lipid-phase transport can occur with no transbilayer transport, whereas Model 2 entails maximum transbilayer transport. Model calculations are exemplified by characterizing the skin permeability of four representative permeants: water, ethanol, nicotinamide, and testosterone. A comparison with experimental steady state permeability and partition data supports that the transport properties of the SC lipids are highly anisotropic, with lateral diffusivities several orders of magnitude higher than the equivalent diffusivity calculated from transbilayer hopping. Nevertheless, the calculations suggest that corneocyte-phase transport plays a major role for all four permeants. These results confirm our previous calculations on water permeability and present a marked contrast to the commonly stated doctrine that the SC transport pathway is primarily intercellular.

Cell Membrane Permeability↗