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PubMed1977

Ionic permeability of K, Na, and Cl in crayfish nerve. Regulation by membrane fixed charges and pH.

Teorell's fixed charge theory for membrane ion permeability was utilized to calculate specific ionic permeabilities from measurements of membrane potential, conductance, and specific ionic transference numbers. The results were compared with the passive ionic conductances calculated from the branched equivalent circuit membrane model of Hodgkin Huxley. Ionic permeabilities for potassium, sodium, and chloride of crayfish (Procambarus clarkii) medial giant axons were examined over an external pH range from 3.8 to 11.4. Action potentials were obtained over this pH range. Failures occurred below pH 3.8 during protonation of membrane phospholipid phosphate and carboxyl, and above pH 11.4 from calcium precipitation. In general, chloride permeability increases with membrane protonation, while cation permeability decreases. At pH 7.0, PK = 1.33 X 10(-5), PCl = 1.49 X 10(-6), PNa = 1.92 X 10(-8) cm/s. PK: PCl: PNa = 693:78:1. PCl is zero above pH 10.6 and is opened predominately by protonation of epsilon-amino, and partially by tyrosine and sulfhydryl groups from pH 10.6 to 9. PK is activated in part by ionization of phospholipid phosphate and carboxyl around pH 4, then further by imidazole from pH 5 to 7, and then predominately from pH 7 to 9 by most probably phosphatidic acid. PNa permeability parallels that of potassium from pH 5 to 9.4. Below pH 5 and above pH 9.4, PNa increases while PK decreases. Evidence was obtained that these ions possibly share common passive permeable channels. The data best support the theory of Teorell, that membrane fixed charges regulate permiability and that essentially every membrane ionizable group appears involved in various amounts in ionic permeability control.

Action Potentials↗
PubMed2000

Ionic permeability of the opossum sciatic nerve perineurium, examined using electrophysiological and electron microscopic techniques.

A parallel electrophysiological and electron microscopic study was used to assess the ionic permeability of the sciatic nerve perineurium of the opossum Monodelphis domestica. The electrophysiological method was used to monitor permeability to K(+), followed by combined electron microscopy and X-ray probe analysis to monitor permeability to the electron-dense tracer lanthanum. Isolated but intact nerves were mounted in a 'grease gap' chamber for extracellular measurement of DC potential and compound action potential (CAP). Challenge with 100 mM [K(+)] Ringer was used to assess the K(+) permeability of the perineurium, since a change in DC potential (DeltaDC) under these conditions reflected changes in the axonal resting membrane potential. There was no detectable change in DC potential or CAP to the first K(+) challenge (n=71 nerves) indicating negligible K(+) permeability under control conditions. The inflammatory mediators histamine 0.1-40 mg/ml (1. 3-130 mM), bradykinin (0.1-4.7 mM) and 5HT (serotonin) 0.1-5.0 mg/ml (0.5-23.5 mM) caused no measurable DeltaDC on subsequent challenge with 100 mM [K(+)] Ringer, indicating no effect on perineurial K(+) permeability. In nerves exposed to the bile salt sodium deoxycholate (DOC, 6 min, 4 mM), challenge with elevated K(+) Ringer caused a dose-dependent DeltaDC in the range 10-100 mM [K(+)] (1.67+/-0.17 mV in 100 mM [K(+)], n=20), indicating increased perineurial permeability caused by DOC, but the response was smaller than that previously reported for the frog perineurium. Lanthanum was observed in the outer layers of the perineurium, but was not seen to penetrate the endoneurium in any of the nerves examined (n=51), even after DOC application. This study shows that the combined electrophysiological and electron microscopic technique for monitoring ionic permeability can be applied to mammalian nerve, and suggests that the opossum perineurium is more resistant to tight junction opening by chemical modulators than is the frog perineurium.

Animals↗
PubMed2001

Permeability of the peptidic GH secretagogues hexarelin and EP 51389, across rat jejunum.

The intestinal permeability of hexarelin and EP 51389, two growth hormone releasing hexa- and tri- peptide analogues, was assessed in vitro with side-by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P-gp) was evaluated by rhodamine 123 accumulation on monolayers of CH(R)C5 cells with increasing concentrations of EP 51389. Hexarelin and EP 51389 permeability were found to be < 1%. Permeability coefficients (P(app)) were 18.87 +/- 2.86 (x10(-7) cm/s) and 5.87 +/- 0.45 (x10(-7) cm/s) for hexarelin and EP 51389, respectively. Bidirectional studies revealed that hexarelin transport was similar in both directions. EDTA did not influence hexarelin permeability. Permeability was predominantly secretory for EP 51389 as P(app) in the BL-to-AP direction [32.56 +/- 6.11 (x10(-7) cm/s)] was greater than AP-to-BL. Confirming involvement of a secretory transport system, chlorpromazine inhibited EP 51389 transport across the jejunum. EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine in CH(R)C5 cells. These results suggest that: 1) the intestinal permeability of hexarelin and EP 51389 is poor; 2) the passage of hexarelin is mainly via a transcellular passive pathway since the contribution of paracellular permeability to the overall permeability is rather low; 3) P-gp may act as a potential barrier for the intestinal absorption of EP 51389.

Animals↗
PubMed1999

Use of Caco-2 cells and LC/MS/MS to screen a peptide combinatorial library for permeable structures.

The transepithelial transport of a synthetic peptide combinatorial library containing 375,000 individual peptides was assessed using Caco-2 cell monolayers in order to screen for permeability and deliverability. A series of 150 pools, each containing 2500 tripeptide sequences, were applied to the apical side of Caco-2 monolayers. Basolateral side samples were collected after 4 h and screened by capillary high-pressure liquid chromatography. The majority of pools showed no permeable species, due to low solubility, limited permeability and extensive metabolism. Several pools contained permeable structure, and transport proved reproducible with passage number and time. Permeable structures were identified by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). To discriminate between isobaric structures, several tripeptides were resynthesized and tested as discrete compounds. For example, 1-2% D-Phe-D-Ala-D-Ser-OH was transported across the Caco-2 cell monolayer with a Papp value of 0.35-0.69 x 10(-6) cm/s, which is comparable with the permeability of amino acids (Leu, Papp = 0.30 x 10(-6) cm/s) and dipeptides (L-Val-L-Val, Papp = 0.18 x 10(-6) cm/s) (Lennernas, H., Palm, K., Fagerholm, U., Artursson, P., 1996. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int. J. Pharm. 127, 103-107; Tamura, K., Bhatnagar, P.K., Takata, J.S., Lee, C.P., Smith, P.L., Borchardt, R.T., 1996. Metabolism, uptake, and transepithelial transport of the diastereomers of Val-Val in the human intestinal cell line Caco-2. Pharm. Res. 13, 1213-1218). These studies demonstrate the techniques used to screen combinatorial libraries for permeability across Caco-2 cells and structurally identify the resulting compounds. Such methodology can be of importance in the achievement of structure-permeability relationships, useful in the design of pharmaceutically bioavailable drugs.

Administration, Oral↗
PubMed2003

Effect of chronic administration of tacrolimus and cyclosporine on human gastrointestinal permeability.

The antirejection drug tacrolimus (FK506) has been reported to impair intestinal permeability in an early stage after orthotopic liver transplantation (OLT), and cyclosporine (CsA) has shown a similar effect in animals. We studied the chronic effect of FK506 and CsA on gastroduodenal and intestinal permeability and on blood endotoxin levels in patients 2 to 3 years after OLT. Thirty-two OLT patients (22 men and 10 women; mean age, 44.8 +/- 7.1) who had received CsA (n = 19) or FK506 (n = 13) and 10 healthy volunteers (6 male and 4 female, mean age 41.7 +/- 5.4) were assessed for gastroduodenal permeability by recovery in urine of sucrose after oral administration and for intestinal permeability by recovery in urine after oral loads of rhamnose and lactulose, which evaluate the intracellular and paracellular routes, respectively. In all subjects, plasma levels of endotoxins also were assessed. Gastroduodenal permeability was similar in patients and controls (0.03 +/- 0.003 versus 0.04 +/- 0.01%, P = NS). In regard to intestinal permeability, passage through the intracellular route was significantly reduced in OLT patients compared with controls (1.13 +/- 0.06 versus 2.74 +/- 0.17%, P <.01), but paracellular permeability was unchanged (0.14 +/- 0.007 versus 0.13 +/- 0.01%, P = NS). Serum endotoxin levels were similar in all subjects. We conclude that chronic administration of FK506 or CsA induces a clinically irrelevant, selective dysfunction of monosaccharide absorption, but does not affect gastroduodenal or intestinal permeability.

Adolescent↗
PubMed2006

Heteromeric, but not homomeric, connexin channels are selectively permeable to inositol phosphates.

Previous work has shown that channels formed by both connexin (Cx)26 and Cx32 (heteromeric Cx26/Cx32 hemichannels) are selectively permeable to cAMP and cGMP. To further investigate differential connexin channel permeability among second messengers, and the influence of connexin channel composition on the selectivity, the permeability of inositol phosphates with one to four phosphate groups through homomeric Cx26, homomeric Cx32, and heteromeric Cx26/Cx32 channels was examined. Connexin channels were purified from transfected HeLa cells and from rat, mouse, and guinea pig livers, resulting in channels with a broad range of Cx26/Cx32 aggregate ratios. Permeability to inositol phosphates was assessed by flux through reconstituted channels. Surprisingly, myoinositol and all inositol phosphates tested were permeable through homomeric Cx32 and homomeric Cx26 channels. Even more surprising, heteromeric Cx26/Cx32 channels showed striking differences in permeability among inositol phosphates with three or four phosphate groups and among isomers of inositol triphosphate. Thus, heteromeric channels are selectively permeable among inositol phosphates, whereas the corresponding homomeric channels are not. There was no discernible difference in the permeability of channels with similar Cx26/Cx32 ratios purified from native and heterologous sources. The molecular selectivity of heteromeric channels among three inositol triphosphates could not be accounted for by simple connexin isoform stoichiometry distributions and therefore may depend on specific isoform radial arrangements within the hexameric channels. Dynamic regulation of channel composition in vivo may effectively and efficiently modulate intercellular signaling by inositol phosphates.

Animals↗
PubMed2006

Effective permeability of porous media containing branching channel networks.

We study the effective permeability of two-dimensional binary systems characterized by a network of branching channels embedded in a uniform matrix material. Channels are assigned a higher permeability than the surrounding matrix and, therefore, serve as preferential pathways for fluid migration. The channel networks are constructed using a nonlooping invasion percolation model. We perform extensive numerical flow simulations to determine the effective permeability tensor of channel-matrix systems with broadly varying network properties. These computed effective permeabilities are then used to systematically investigate the factors that control the permeability upscaling process. The upscaling framework adopted for this study is based on spatial power averaging. We determine the scaling behavior of the averaging exponent omega by analyzing its dependence on three characteristic properties of the channel-matrix system: (i) the channel-matrix permeability contrast; (ii) the fractal dimension of the channel network, df; and (iii) the average tortuosity of spanning paths on the network backbone, tau. The behavior of and the corresponding component of effective permeability in each principal direction (parallel and perpendicular to the network-spanning direction) are compared. The permeability anisotropy ratio is shown to be a clear function of key system properties.

Journal Article↗
PubMed1987

Regulation of Soybean Nitrogen Fixation in Response to Rhizosphere Oxygen: II. Quantification of Nodule Gas Permeability.

Nodule nitrogen fixation rates are regulated by a mechanism which is responsive to the rhizosphere oxygen concentration. In some legumes, this oxygen-sensitive mechanism appears to involve changes in the gas permeability of a diffusion barrier in the nodule cortex. In soybean evidence for such a mechanism has not been found. The purpose of this research was to make quantitative measurements of soybean nodule gas permeability to test the hypothesis that soybean nodule gas permeability is under physiological control and responsive to the rhizosphere oxygen concentration. Intact hydroponically grown soybean plants were exposed to altered rhizosphere oxygen concentrations, and the nodule gas permeability, acetylene reduction and nodule respiration rates were repeatedly assayed. After a change in the external oxygen concentration, nitrogenase activity and nodule respiration rates displayed a short-term transient response after which the values returned to rates similar to those observed under ambient oxygen conditions. In contrast to steady-state nitrogenase activity and nodule respiration, nodule gas permeability was dramatically affected by the change in oxygen concentration. Decreasing the external oxygen concentration to 0.1 cubic millimeter per cubic millimeter resulted in a mean increase in nodule gas permeability of 63%. Increasing the rhizosphere oxygen concentration resulted in decreased nodule gas permeability. These data are consistent with the hypothesis that soybean nodules are capable of regulating nitrogen fixation and nodule respiration rates in response to changes in the rhizosphere oxygen concentration and indicate that the regulatory mechanism involves physiological control of the nodule gas permeability.

Journal Article↗
PubMed1987

Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients.

The blood-retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5-10 times the normal value. Onset of diabetes in the decade before and after puberty did not change the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood-retinal barrier correlated well with changes in retinal morphology as seen by ophthalmoscopy and fluorescein angiography. However, there was an overlap in permeability between groups with different retinal appearance. A significant factor was the presence of macular edema, which also apparently indicated a preproliferative state.

Adolescent↗
PubMed2005

Permeability of ionized salicylate derivatives through guinea pig dorsal skin.

pH-dependency of skin permeability to salicylic acid was examined in excised guinea pig dorsal skin. Permeation followed the pH-partition theory at acidic pH. However, above pH 5.0 the observed permeability coefficients were larger than the estimated values obtained from the ratio of the undissociated forms. These findings are quite different from those obtained using the same drug and a silicone rubber membrane, in which permeability coefficients were consistent with the pH-partition theory. The findings suggested that permeation of salicylate as anions occurred at a neutral skin pH. The permeability coefficient of the ionized form was estimated to be about 1.6% of the nonionized form. We also examined the skin permeability of salicylate and its five 5-substituents and two 3-substituents at pH 7.4. We investigated the relationship between their permeability coefficients and the physico-chemical properties of the substituents. Multi regression analysis on the permeability coefficients showed a parabolic relationship between the values of the hydrophobic parameter (pi) and the logarithms of the permeability coefficients. These findings suggested that the ionic permeation pathway of salicylate derivatives is controlled by hydrophobic as well as hydrophilic properties.

Algorithms↗
PubMed1986

Carriers of X-linked retinitis pigmentosa. A fluorophotometric determination of the permeability of the blood-retinal barrier.

The blood-retinal barrier permeability to fluorescein was studied in a single family with X-linked retinitis pigmentosa by an elaborate vitreous fluorophotometric method. Affected males showed a ten times increase of permeability compared with normals. In a group of seven obligate carriers the mean permeability was significantly increased by 45% compared with the mean permeability in a group of normals. Five of the seven carriers had permeabilities higher than the normal mean permeability + 2 SD, while two carriers had a permeability within the normal mean +/- 2 SD. Thus, this study supported that carriers of X-linked retinitis pigmentosa show deterioration of the blood-retinal barrier. However, the phenomenon is not present in all carriers and the permeability cannot be used as a completely safe indicator of the carrier state.

Adolescent↗
PubMed1980

The relationship between mitochondrial membrane permeability, membrane potential, and the retention of Ca2+ by mitochondria.

Ca2+ release from liver mitochondria induced by N-ethylmaleimide, diamide, inorganic phosphate, palmitoyl-coenzyme A, and oxaloacetate occurs by a common mechanism. With all agents, a collapse of membrane potential, uptake of hydrogen ion, progressive acceleration of respiration, and large amplitude swelling accompanies Ca2+ release. These findings indicate that the agents promote an increase in the permeability of the inner membrane and that Ca2+ release can be explained under these conditions without invoking the action of a Ca2+ release carrier. The increase in permeability produced by the Ca2+-releasing agents requires the accumulation of exogenouse Ca2+. Sr2+ and Mn2+ cannot substitute for Ca2+ and the permeability increase is prevented by nupercaine. Free fatty acid accumulation in the mitochondria accompanies the increase in permeability. Polyunsaturated fatty acids accumulate more rapidly than saturated plus monounsaturated fatty acids, which indicates the accumulation of 1-acyllysophospholipid. Any inhibitor or condition which prevents the permeability change also prevents the accumulation of lysophospholipid, suggesting that these compounds cause the permeability increase. As Ca2+ release and swelling proceed, there is an accompanying oxidation of pyridine nucleotides. This oxidation occurs both with releasing agents which can oxidize the nucleotides through the action of mitochondrial enzymes as well as with agents which cannot. Any inhibitor or condition which prevents the increase in permeability also largely prevents the oxidation of pyridine nucleotides. The increase in the NAD(P)+/NAD(P)H ratio produced by the releasing agents can be explained as an effect secondary to the increase in permeability and collapse of the mitochondrial pH gradient rather than a primary cause of Ca2+ release.

Animals↗
PubMed1995

Identification of the structural elements of amphotericin B and other polyene macrolide antibiotics of the hepteane group influencing the ionic selectivity of the permeability pathways formed in the red cell membrane.

The selectivity of the transmembrane permeability induced by polyene antibiotics was studied in human erythrocytes and related to the hemolytic potency of the drugs. The selectivity induced was differently, dependent on the antibiotic structure in aromatic (vacidin A, gedamycin) and nonaromatic heptaenes (amphotericin B, candidin). Aromatic heptaenes were more effective than nonaromatic in inducing permeability to K+. For both groups of antibiotics, permeability to K+ was not affected by substitution at the carboxyl group but important differences in the induction of permeability to H+, OH- and Cl- were found. The strongly hemolytic aromatic heptaenes vacidin A and gedamycin exhibited much higher protonophoric activity than the nonaromatic ones: amphotericin B, and candidin. The protonophoric properties of aromatic heptaenes were related to the presence of a free carboxyl group in the antibiotic molecule. Indeed the esterification or amidation of the carboxyl group of vacidin A or gedamycin eliminated the ability of the antibiotic to increase H+ conductance and consequently diminished their hemolytic activity to an important extent. Both groups of antibiotics differed also in the efficiency of anion permeability induction. Only unsubstituted aromatic heptaenes, at high concentration, induced Cl-/OH- exchange and conductive flux of Cl- in a concentration-dependent manner. Substitution at the carboxyl group of vacidin A or gedamycin eliminated this property. Amphotericin B as well as its carboxyl-substituted derivatives formed a pathway characterized by low K+ over Cl- selectivity, whatever the concentration. The hemolytic activity, related to K+ permeability increased by heptaenes was dependent on simultaneous increase of the permeability to anions, and net KCl influx. Carboxyl-substituted derivatives of aromatic heptaenes presenting a remarkably high selectivity for K+, had consequently a very poor hemolytic activity.

Amphotericin B↗
PubMed2005

Modeling Caco-2 permeability of drugs using immobilized artificial membrane chromatography and physicochemical descriptors.

This study evaluates the potential of immobilized artificial membrane (IAM) chromatography, in combination with other physicochemical descriptors for high-throughput absorption profiling during lead optimization. An IAM chromatographic method was developed and validated. Absorption profiles of 32 structurally diverse compounds (acidic, basic, neutral and amphoteric) were then evaluated based on their IAM retention factor (log k'IAM), molecular weight (MW), calculated log P (C log P), polar surface area (PSA), hydrogen bonding capacity (HBD and HBA) and calculated Caco-2 permeability (QPCaco). Using regression and stepwise regression analysis, experimental Caco-2 permeability was correlated against log k'IAM and a combination of various physicochemical variables for quantitative structural-permeability relationship (QSPR) study. For the 32 structurally diverse compounds, log k'IAM correlated poorly with Caco-2 permeability values (R2 = 0.227). Stepwise regression analysis confirmed that Clog, PSA, HBD and HBA parameters are not statistically significant and can be eliminated. Correlation between Caco-2 cell uptake and log k'IAM was enhanced when molecular size factor (MW) was included (R2 = 0.555). The exclusion of 11 compounds (paracellularly and actively transported, Pgp substrates and blocker, and molecules with MW lesser than 200 and greater than 800) improved the correlation between Caco-2 permeability, IAM and MW factors to R2 value of 0.84. The results showed that IAM chromatography can only profile the passive absorption of drug molecules. Finally, it was confirmed in this study that the IAM model can accurately identify the Caco-2 permeability of nontransported Pgp substrates, such as verapamil and ketoconazole, through passive permeation because of their high permeability. IAM chromatography, combined with molecular size factor (MW), is useful for elucidating biopartitioning mechanism of drugs.

Caco-2 Cells↗
PubMed2004

Estimation of the human intestinal permeability of butyltin species using the Caco-2 cell line model.

The main objective of the work was the setup of the Caco-2 human intestinal cell-line model for the study of the intestinal permeation of monobutyltin (MBT), dibutyltin (DBT) and tributyltin (TBT). The study was focused in gathering information on (a) the relative permeability of butyltins, (b) their possible permeation routes (paracellular/transcellular) and (c) the eventual interactions between the different butyltins when occurring as a mixture. The presence of basolateral serum protein greatly influenced the permeability, causing a large net clearance, but the apparent permeability (Papp) values were comparable to that of phenolred, suggesting a low in vivo permeability of the butyltins. The found permeability pattern correlates well with the general in vivo toxicity pattern (trialkyltin>dialkyltin>>monoalkyltin). The accumulation pattern (DBT>TBT>MBT) was different from that of permeability and may be an important element regarding the elucidation of some specific strong toxic effects caused by the dialkyltins in several species. The transport of MBT and DBT was found to be dependent on the paracellular route status. An interaction between the butyltin compounds in a mixture was found for the accumulation results (the accumulation was significantly higher for the three compounds when in a mixture). A set of useful information about the butyltin accumulation and transport by the epithelial Caco-2 cell line was, thus, achieved, constituting a starting point for future research on the permeability of butyltins from contaminated food and beverages.

Biological Transport↗
PubMed2006

A novel fluorescence-based cellular permeability assay.

Vascular permeability is a pathologic process in many disease states ranging from metastatic progression of malignancies to ischemia-reperfusion injury. In order to more precisely study tissue, and more specifically cell layer permeability, our goal was to create a fluorescence-based assay which could quantify permeability without radioactivity or electrical impedance measurements. Human aortic endothelial cells were grown in monolayer culture on Costar-Transwell clear polyester membrane 6-well cell culture inserts. After monolayer integrity was confirmed, vascular endothelial growth factor (VEGF(165)) at varying concentrations with a fixed concentration of yellow-green fluorescent 0.04 microm carboxylate-modified FluoSpheres microspheres were placed in the luminal chamber and incubated for 24 h. When stimulated with VEGF(165) at 20, 40, 80, and 100 ng/ml, this assay system was able to detect increases in trans-layer flux of 8.2+/-2.4%, 16.0+/-3.7%, 41.5+/-4.9%, and 58.6+/-10.1% for each concentration, respectively. This represents the first fluorescence-based permeability assay with the sensitivity to detect changes in the permeability of a cell layer to fluid flux independent of protein flux; as well as being simpler and safer than previous radioactive-and impedance-based permeability assays. With the application of this in vitro assay to a variety of pathologic conditions, both the dynamics and physiology relating to cellular permeability can be more fully investigated.

Biophysics↗
PubMed1998

Urea and water permeability in dogfish (Squalus acanthias) gills.

We used a perfused gill preparation from dogfish to investigate the origin of low branchial permeability to urea. Urea permeability (14C-urea) was measured simultaneously with diffusional water permeability (3H2O). Permeability coefficients for urea and ammonia in the perfused preparation were almost identical to in vivo values. The permeability coefficient of urea was 0.032 x 10(-6) cm/sec and of 3H2O 6.55 x 10(-6) cm/sec. Adrenalin (1 x 10(-6) M) increased water and ammonia effluxes by a factor of 1.5 and urea efflux by a factor of 3.1. Urea efflux was almost independent of the urea concentration in the perfusion medium. The urea analogue thiourea in the perfusate had no effect on urea efflux, whereas the non-competitive inhibitor of urea transport, phloretin, increased efflux markedly. The basolateral membrane is approximately 14 times more permeable to urea than the apical membrane. We conclude that the dogfish apical membrane is extremely tight to urea, but the low apparent branchial permeability may also relate to the presence of an active urea transporter on the basolateral membrane that returns urea to the blood and hence reduces the apical urea gradient.

Animals↗
PubMed2001

In vitro intestinal permeability of factor Xa inhibitors: influence of chemical structure on passive transport and susceptibility to efflux.

PURPOSE: To study the in vitro intestinal permeability of a number of newly synthesised factor Xa inhibitors to better understand the poor oral absorption of these compounds. METHODS: The bidirectional transport of the fXa inhibitors was studied in the Caco-2 cell model and isolated rat ileal tissue. An attempt was made to characterize efflux mechanisms with the help of commonly used substrates and inhibitors of various transport proteins. In addition, the transport of the fXa inhibitors was studied in MDCK cells transfected with the human MDR1 gene and expressing large amounts of P-glycoprotein (Pgp). RESULTS: The in vitro absorptive permeability was low for all but one of the fXa inhibitors. For compounds with non-substituted amidine, a charge (due to ionisation at neutral pH) may have resulted in poor membrane partitioning. Neutral compounds with substituted amidines were effluxed from the epithelial cells. The significance of the secretion process was illustrated by the results obtained for a neutral analogue showing high absorptive Caco-2 cell permeability that was not obviated by efflux. Transport inhibition studies in Caco-2 and permeability studies in the MDR1-transfected MDCK cells consistently showed that Pgp is not involved in the secretion of fXa inhibitors. Besides efflux, metabolic liability limited the permeation of the neutral lipophilic analogues with a carbamate ester. CONCLUSIONS: Poor intestinal permeability may be an important factor in the incomplete oral absorption of the bisbenzimidazole-type fXa inhibitors. Poor permeability may be related to poor membrane partitioning for hydrophilic analogues, whereas susceptibility to efflux transports and gastro-intestinal enzymatic degradation may limit the permeability of some of the neutral less hydrophilic derivatives.

Animals↗