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PubMed1996

Intestinal permeability, circulating endotoxin, and postoperative systemic responses in cardiac surgery patients.

OBJECTIVES: To determine whether intestinal permeability increases during cardiac operations, and whether the degree of endotoxemia is related to this increase. Furthermore, to determine whether intestinal permeability is related to the hemodynamic state during operation and to postoperative systemic responses. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Twenty-three male patients undergoing elective coronary artery bypass surgery. INTERVENTIONS: Before surgery and during the fifth postoperative day, 100 mL of a solution containing L-rhamnose and cellobiose were administered orally. MEASUREMENTS AND MAIN RESULTS: Intestinal permeability was assessed by measuring the urinary excretion of L-rhamnose and cellobiose. Endotoxin concentrations in blood and prime fluid, hemodynamics, oxygen consumption, gas exchange, fluid balance, and the dose of vasoactive drugs were measured. Systemic responses were assessed by measuring hypermetabolism, circulatory support, and gas exchange. Intestinal permeation of cellobiose, reflecting paracellular transport, significantly increased during operation (p < 0.01), and correlated with the amount of circulating endotoxin (r2 = 0.46; p < 0.01). A high dose of ephedrine administered during operation, low baseline central venous pressure, and a less positive fluid balance during operation were associated with high intestinal permeability (r2 = 0.7; p < 0.01). Intestinal permeability was related to postoperative systemic responses (r2 = 0.49; p < 0.01). CONCLUSIONS: This study shows that during elective coronary artery bypass operations intestinal permeability between cells may increase. The degree of endotoxemia is related to this increase. Increased intestinal permeability is related to the use of ephedrine, especially during hypovolemia, and to postoperative systemic responses. Although a causative relation is not shown, these results might indicate that hypovolemia and vasoconstriction should be avoided during the operation.

Aged↗
PubMedDate not supplied

Intestinal microcirculation and gut permeability in acute pancreatitis: early changes and therapeutic implications.

Translocation of bacteria from the intestine causes local and systemic infection in severe acute pancreatitis. Increased intestinal permeability is considered a promoter of bacterial translocation. The mechanism leading to increased gut permeability may involve impaired intestinal capillary blood flow. The aim of this study was to evaluate and correlate early changes in capillary blood flow and permeability of the colon in acute rodent pancreatitis of graded severity. Edematous pancreatitis was induced by intravenous cerulein; necrotizing pancreatitis by intravenous cerulein and intraductal glycodeoxycholic acid. Six hours after induction of pancreatitis, the permeability of the ascending colon was assessed by the Ussing chamber technique; capillary perfusion of the pancreas and colon (mucosal and subserosal) was determined by intravital microscopy. In mild pancreatitis, pancreatic capillary perfusion remained unchanged (2.13 c 0.06 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P = NS), whereas mucosal (1.59 +/-0.03 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control]; P <0.01) and subserosal (2.47 +/-0.04 vs. 3.74 +/-0.05 nl x min(-1) x cap((-1))[control]; P <0.01) colonic capillary blood flow was significantly reduced. Severe pancreatitis was associated with a marked reduction in both pancreatic (1.06 +/-0.03 vs. 1.98 +/-0.04 nl x min(-1) x cap(-1) [control]; P <0. 01) and colonic (mucosal: 0.59 +/-0.01 vs. 2.28 +/-0.03 nl x min(-1) x cap((-1))[control], P <0.01; subserosal: 1.96 +/-0.05 vs. 3.74 +/-0.05 nl x min(-1) x cap(-1) [control], P <0.01) capillary perfusion. Colon permeability tended to increase with the severity of the disease (control: 147 +/-19 nmol x thr(-1) x cm(-2); mild pancreatitis: 158 +/-23 nmol x hr(-1) x cm(-2); severe pancreatitis: 181 +/-33 nmol x hr(-1) x cm(-2); P = NS). Impairment of colonic capillary perfusion correlates with the severity of pancreatitis. A decrease in capillary blood flow in the colon, even in mild pancreatitis not associated with significant protease activation and acinar cell necrosis or impairment of pancreatic capillary perfusion, suggests that colonic microcirculation is especially susceptible to inflammatory injury. There was no significant change in intestinal permeability in the early stage of pancreatitis, suggesting a window of opportunity for therapeutic interventions to prevent the later-observed increase in gut permeability, which could result in improved intestinal microcirculation.

Acute Disease↗
PubMed2003

Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability.

Hydrogen bonding has been identified as an important parameter for describing drug permeability. Recently, we derived models for predicting intestinal permeability using the hydrogen bonding descriptors polar surface area (PSA) and number of hydrogen bond donors (HBD), and a lipophilicity descriptor [J. Med. Chem. 41 (1998) 4939]. We have now explored other types of hydrogen bonding descriptors to see if these improve the models. Both an experimental hydrogen bonding descriptor, deltalogP, and calculated descriptors, based either on semiempirical calculations or on experimentally derived hydrogen bond strength values of small molecules, were used. Principal component analyses (PCA) were performed in order to characterize the different parameters, using both a drug data set and a data set of small non-drug-like molecules for which deltalogP-values had been published. For a set of diverse drug molecules, for which human intestinal permeability data was available, a PLS-analysis was performed to study the correlation of permeability to the different hydrogen bonding parameters. No correlation could be identified between deltalogP and human intestinal permeability in this data set. However, the combination of a hydrogen bond donor descriptor, a general hydrogen bonding descriptor and a lipophilicity descriptor enabled the prediction of human intestinal permeability, whereas hydrogen bond acceptor descriptors were found to be less important. The obtained models successfully predicted the intestinal permeability values of two external data sets.

Biological Transport↗
PubMed2003

How to determine the permeability for cement infiltration of osteoporotic cancellous bone.

Cement augmentation is an emerging surgical procedure in which bone cement is used to infiltrate and reinforce osteoporotic vertebrae. Although this infiltration procedure has been widely applied, it is performed empirically and little is known about the flow characteristics of cement during the injection process. We present a theoretical and experimental approach to investigate the intertrabecular bone permeability during the infiltration procedure. The cement permeability was considered to be dependent on time, bone porosity, and cement viscosity in our analysis. In order to determine the time-dependent permeability, ten cancellous bone cores were harvested from osteoporotic vertebrae, infiltrated with acrylic cement at a constant flow rate, and the pressure drop across the cores during the infiltration was measured. The viscosity dependence of the permeability was determined based on published experimental data. The theoretical model for the permeability as a function of bone porosity and time was then fit to the testing data. Our findings suggest that the intertrabecular bone permeability depends strongly on time. For instance, the initial permeability (60.89 mm(4)/N(*)s) reduced to approximately 63% of its original value within 18 seconds. This study is the first to analyze cement flow through osteoporotic bone. The theoretical and experimental models provided in this paper are generic. Thus, they can be used to systematically study and optimize the infiltration process for clinical practice.

Aged↗
PubMed2000

The lipopolysaccharide barrier: correlation of antibiotic susceptibility with antibiotic permeability and fluorescent probe binding kinetics.

Lipopolysaccharide (LPS), the primary lipid on the surface of Gram-negative bacteria, is thought to act as a permeability barrier, making the outer membrane relatively impermeable to hydrophobic antibiotics, detergents, and host proteins. Mutations in the LPS biosynthetic apparatus increase bacterial susceptibility to such agents. To determine how this increased susceptibility is mediated, we have correlated antibiotic susceptibilities of rough (antibiotic resistant) and deep rough (antibiotic susceptible) bacterial strains with antibiotic permeabilities and fluorescent probe binding kinetics for bilayers composed of LPS purified from the same strains. Bilayer permeabilities of two hydrophobic beta-lactam antibiotics were measured by encapsulating the appropriate beta-lactamases in large unilamellar vesicles. In the presence of MgCl(2), permeabilities of LPS bilayers from rough and deep rough bacteria were similar and significantly lower than those of bacterial phospholipids (BPL). Addition of BPL to the LPS bilayers increased their antibiotic permeability to approximately the level of the BPL bilayers. Binding rates of the fluorescent probe bis-aminonaphthylsulfonic acid (BANS) were 2 orders of magnitude slower for both rough and deep rough LPS bilayers compared to that of bilayers composed of BPL or mixtures of LPS and BPL. On the basis of these results and the observation that deep rough bacteria have higher levels of phospholipid on their surface than do rough bacteria (Kamio, Y., and Nikaido, H. (1976) Biochemistry 15, 2561-2569), we argue that the high susceptibility of deep rough bacteria is due to the presence of phospholipids on their surface. Experiments with phospholipid bilayers showed that the addition of PEG-lipids (containing covalently attached hydrophilic polymers) had little effect on permeability and binding rates, whereas the addition of cholesterol reduced permeability and slowed binding to levels approaching those of LPS. Therefore, we argue that the barrier provided by LPS is primarily due to its tight hydrocarbon chain packing (Snyder et al., (1999) Biochemistry 38, 10758-10767) rather than to its polysaccharide headgroup.

Anti-Bacterial Agents↗
PubMed1996

Effects of submicellar bile salt concentrations on biological membrane permeability to low molecular weight non-ionic solutes.

Bile salts have been hypothesized to mediate cytotoxicity by increasing membrane permeability to aqueous solutes. We examined whether submicellar bile salt concentrations affect model and native membrane permeability to small uncharged molecules such as water, urea, and ammonia. Osmotic water permeability (Pf) and urea permeability were measured in large unilamellar vesicles composed with egg yolk phosphatidylcholine (EYPC) +/- cholesterol (Ch) or rat liver microsomal membranes by monitoring self-quenching of entrapped carboxyfluorescein (CF). Ammonia permeability was determined utilizing the pH dependence of CF fluorescence. Submicellar bile salt concentrations did not significantly alter Pf of EYPC +/- Ch or rat liver microsomal membranes. At taurodeoxycholate (TDC) or tauroursodeoxycholate concentrations approaching those that solubilized membrane lipids, CF leakage occurred from vesicles, but Pf remained unchanged. Higher bile salt concentrations (0.5-2 mM TDC) did not alter Pf of equimolar EYPC/Ch membranes. The activation energy for transmembrane water flux was unchanged (12.1 +/- 1.2 kcal/mol for EYPC) despite the presence of bile salts in one or both membrane hemileaflets, suggesting strongly that bile salts do not form transmembrane pores that facilitate water flux. Furthermore, submicellar bile salt concentrations did not increase membrane permeability to urea or ammonia. We conclude that at submicellar concentrations, bile salts do not form nonselective convective channels that facilitate transmembrane transport of small uncharged molecules. These results suggest that bile salt-mediated transport of specific substrates, rather than nonselective enhancement of membrane permeability, underlies bile salt cytotoxicity for enterocytes and hepatocytes.

Ammonia↗
PubMed2002

Structure-activity relationship for enhancement of paracellular permeability across Caco-2 cell monolayers by 3-alkylamido-2-alkoxypropylphosphocholines.

Paracellular permeability enhancers have been used to improve the oral bioavailability of hydrophilic drugs; however, the mechanism of action of many enhancers is poorly understood. In this study, highly potent enhancers of paracellular permeability were identified in the 3-alkylamido-2-alkoxypropylphosphocholine series, and a structure-activity relationship was developed for enhancement of paracellular permeability across Caco-2 cell monolayers. Compounds with short (<5 carbons) hydrocarbon chains at both C-2 and C-3 were generally inactive. The potency exhibited a parabolic relationship with respect to the chain length at either C-2 or C-3. Linear molecules (i.e., compounds with a short hydrocarbon chain at C-2 or C-3 and a long hydrocarbon chain on C-3 or C-2, respectively) were more potent than the corresponding branched molecules with the same carbon load. The efficacy of 3-alkylamido-2-alkoxypropylphosphocholines as enhancers of paracellular permeability was not dependent on their existence in micellar form or their ability to alter the fluidity of cell membrane. Previously, a correlation between the potency of alkylphosphocholines as enhancers of paracellular permeability and the inhibitors of phospholipase C (PLC) was established in Madine Darby canine kidney (MDCK) cell monolayers. The potencies of selected 3-alkylamido-2-alkoxypropylphosphocholines as inhibitors of PLC and enhancers of paracellular permeability fit well into this correlation. Therefore, phosphocholines are likely to increase paracellular permeability by modulating the signal transduction pathway initiated by a PLC-catalyzed reaction rather than by physically altering the cell membrane.

Adenosine Triphosphate↗
PubMed2005

Exploring the role of different drug transport routes in permeability screening.

The influence of different drug transport routes in intestinal drug permeability screening assays was studied. Three experimental models were compared: the small-intestine-like 2/4/A1 cell model, which has a leaky paracellular pathway, the Caco-2 cell model, which has a tighter paracellular pathway, and artificial hexadecane membranes (HDMs), which exclusively model the passive transcellular pathway. The models were investigated regarding their ability to divide passively and actively transported compounds into two permeability classes and to rank compounds according to human intestinal absorption. In silico permeability models based on two-dimensional (2D) and three-dimensional (3D) molecular descriptors were also developed and validated using external test sets. The cell-based models classified 80% of the acceptably absorbed compounds (FA >/= 30%) correctly, compared to 60% correct classifications using the HDM model. The best compound ranking was obtained with 2/4/A1 (r(s) = 0.74; r(s) = 0.95 after removing actively transported outliers). The in silico model based on 2/4/A1 permeability gave results of similar quality to those obtained when using experimental permeability, and it was also better than the experimental HDM model at compound ranking (r(s) = 0.85 and 0.47, respectively). We conclude that the paracellular transport pathway present in the cell models plays a significant role in models used for intestinal permeability screening and that 2/4/A1 in vitro and in silico models are promising alternatives for drug discovery permeability screening.

Administration, Oral↗
PubMed1998

Caco-2 cell permeability of a new (hydroxybenzyl)ethylenediamine oral iron chelator: correlation with physicochemical properties and oral activity.

This study describes the transport of CGP 75254A, a novel oral iron chelator, across Caco-2 cells in an attempt to model intestinal epithelial cell permeability in man. CGP 75254A was dosed to the apical side of Caco-2 cell monolayers, together with [14C]mannitol as an internal permeability standard. The apparent permeability (Papp) was calculated from the cumulative appearance of drug in the basolateral fluid with time. The [14C]mannitol Papp indicated that the Caco-2 monolayers remained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilities of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH values between 5.5 and 7.0. However, at pH 8.0 permeability is predicted as negligible. Cell permeability data are in full accordance with key physicochemical properties of CGP 75254A and suggest that the drug is passively absorbed. The results, which suggest likely quantitative absorption in vivo, are supported by preliminary pharmacological experiments in marmosets.

Administration, Oral↗
PubMedDate not supplied

Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy. Results indicate that the parent pyridine was highly permeable and that chemical substitution was able to reduce pyridine permeability almost 20-fold. The substituent effect on permeability provided the following rank order: 3-COO- < 4-NH2 < 3-CONH2 < 3-Cl < 3-CHO < 3-OH < 3-CH2OH < 3-C6H5 < 3-NH2 < 3-CH2C6H5 < 3-C2H5 < 3-H < 3-CH3 < 3-F < 4-C6H5. This substituent effect was better explained via molecule descriptors from the computational chemistry approach than explained by classic descriptors from Hansch. Computational descriptors indicate that aqueous desolvation, but not membrane partitioning per se, dictated substituent effect on permeability.

Caco-2 Cells↗
PubMed2001

Effect of acute copper exposure on gastrointestinal permeability in healthy volunteers.

In vitro studies indicate that treating cells with copper results in alteration of tight junction permeability. In humans, ingestion of a single bolus of up to 10 mg Cu/L (as copper sulfate) causes nausea and vomiting in approximately 20 and 5% of the volunteers, respectively. To understand better the gastric and intestinal effects of copper, in this study we evaluated in asymptomatic volunteers (1) the effects of acute copper ingestion on gastric and intestinal permeability and (2) whether the appearance of gastrointestinal symptoms is associated with changes in mucosal permeability. Thirty-one asymptomatic subjects were assessed in a randomized, double-blind, crossover study that included two permeability tests, one after ingesting 200 ml distilled water and the other after ingesting 200 ml water containing 10 mg Cu/L (as copper sulfate). Fifteen minutes after ingestion subjects drank a second solution containing 40 g sucrose, 7.5 g lactulose, and 2 g mannitol, and urine was collected for 5 hr. Sugar concentrations were determined by gas chromatography. Symptoms during the trials were recorded in self-administered questionnaires. Ingestion of the 10 mg/L copper solution significantly increased gastric permeability to sucrose [20.8 (11.8-73.4) vs 28.4 (16.6-113.9) mg, respectively; P = 0.0064] but did not change intestinal permeability to lactulose/mannitol [0.87 (0.53-2.06) vs 1.17 (0.58-2.39)%, respectively; P = 0.18]. Gastrointestinal symptoms were reported during both the basal and the experimental conditions, but after copper ingestion they increased to 22.6% of the subjects and were significantly more intense than under basal conditions (P = 0.047). However, changes in permeability were not related to the appearance of symptoms. These results indicate that acute oral exposure to 10 mg Cu/L exerts an effect on gastric but not intestinal mucosa, reducing the gastric mucosal barrier capacity, independently of the appearance of gastrointestinal symptoms.

Adult↗
PubMed1997

Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG 400 determined by jejunal perfusion.

PURPOSE: To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards. METHODS: Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation. RESULTS: The mean P(eff) (+/-SD) of piroxicam, phenylalanine, propranolol, and PEG 400 were 10.40 +/- 5.93, 6.67 +/- 3.42, 3.59 +/- 1.60, 0.80 0.46 x 10(-4) cm/sec, respectively. The coefficient of variation for the intersubject variability, first and second perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine, 52.8% and 57.8%; propranolol, 62.1% and 44.6%; and PEG 400, 81.7% and 42.3%, indicating a slightly lower CV for the second perfusion period in the same subject. The intrasubject CV's between the two perfusion periods were: 19.4%, 21.3%, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied. CONCLUSIONS: Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.

Adult↗
PubMed1997

Theoretical calculation and prediction of Caco-2 cell permeability using MolSurf parametrization and PLS statistics.

PURPOSE: To statistically model the permeability across Caco-2 cell monolayers using theoretically computed molecular descriptors and multivariate statistics. METHODS: Seventeen structurally diverse compounds were investigated. The program MolSurf was used to compute theoretical molecular descriptors related to physico-chemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the permeability across Caco-2 cell monolayers and the theoretically computed molecular descriptors. RESULTS: Excellent statistical models were derived. Properties associated with hydrogen bonding had the largest impact on diffusion through the monolayers and should be kept at a minimum to promote high permeability. High lipophilicity and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to have a favorable influence to achieve high permeability. CONCLUSIONS: The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model permeability across Caco-2 cell monolayers and, thus, differentiate drugs with poor permeability from those with acceptable permeability at an early stage of the preclinical drug discovery process.

Caco-2 Cells↗
PubMed2001

Predicted permeability of the cornea to topical drugs.

PURPOSE: To develop a theoretical model to predict the passive, steady-state permeability of cornea and its component layers (epithelium, stroma, and endothelium) as a function of drug size and distribution coefficient (phi). The parameters of the model should represent physical properties that can be independently estimated and have physically interpretable meaning. METHODS: A model was developed to predict corneal permeability using 1) a newly developed composite porous-medium approach to model transport through the transcellular and paracellular pathways across the epithelium and endothelium and 2) previous work on modeling corneal stroma using a fiber-matrix approach. RESULTS: The model, which predicts corneal permeability for molecules having a broad range of size and lipophilicity, was validated by comparison with over 150 different experimental data points and showed agreement with a mean absolute fractional error of 2.43, which is within the confidence interval of the data. In addition to overall corneal permeability, the model permitted independent analysis of transcellular and paracellular pathways in epithelium, stroma and endothelium. This yielded strategies to enhance corneal permeability by targeting epithelial paracellular pathways for hydrophilic compounds (phi < 0.1 - 1), epithelial transcellular pathways for intermediate compounds, and stromal pathways for hydrophobic compounds (phi > 10 - 100). The effects of changing corneal physical properties (e.g., to mimic disease states or animals models) were also examined. CONCLUSIONS: A model based on physicochemical properties of the cornea and drug molecules can be broadly applied to predict corneal permeability and suggest strategies to enhance that permeability.

Administration, Topical↗
PubMed1989

Transdermal delivery of narcotic analgesics: comparative permeabilities of narcotic analgesics through human cadaver skin.

Relationships between the in vitro permeation rates of select narcotic analgesics through human skin and their physicochemical properties were investigated by following the permeation kinetics of six representative compounds in small diffusion cells. The relative permeability coefficients of three phenylpiperidine analogues, meperidine, fentanyl, and sufentanil, all measured on a single piece of skin, were 3.7 x 10(-3), 5.6 x 10(-3), and 1.2 x 10(-2) cm/hr, respectively. Using membranes from the same skin section, the permeability coefficients of three opioid alkaloids, morphine, codeine, and hydromorphone, were considerably lower, at 9.3 x 10(-6), 4.9 x 10(-5), and 1.4 x 10(-5) cm/hr, respectively. The high permeability coefficients of the former compounds are due to their highly lipophilic nature as reflected in high octanol/water partition coefficients and low solubility parameters. Generally, the permeability coefficients of the narcotics increase as the lipophilicity increases. When viewed in literature perspective, the data suggest that aqueous tissue control of transport is approached in the case of the phenylpiperidine analogues, all of which have Koctanol/water values greater than 40. Permeability coefficients of fentanyl and sufentanil were also determined as a function of pH over the pH range 7.4 to 9.4, in this instance with membranes prepared from additional samples of skin. The permeability coefficients of each drug varied less than threefold over the pH range, a behavior consistent with the highly hydrophobic natures of the compounds. The low permeability coefficients of morphine, codeine, and hydromorphone coupled with their low potencies make these drugs poor transdermal candidates. It appears that fentanyl and sufentanil can be successfully transdermally delivered.

Administration, Cutaneous↗
PubMed1999

Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties.

PURPOSE: To develop a theoretical method for prediction of transcellular permeability to peptides. METHODS: The dynamic molecular surface properties of 19 oligopeptide derivatives, divided into three homologous series were calculated. The dynamic molecular surface properties were compared with commonly used experimental predictors of membrane permeability such as partition coefficients. Relationships between the dynamic molecular surface properties and intestinal epithelial permeability, as determined in Caco-2 cell monolayers, were used to develop a model for prediction of the transmembrane permeability to the oligopeptide derivatives. RESULTS: A theoretical model was derived which takes both the polar and non-polar part of the dynamic molecular surface area of the investigated molecule into consideration. The model provided a strong relationship with transepithelial permeability for the oligopeptide derivatives. The predictability of transepithelial permeability from this model was comparable to that from the best experimental descriptor. CONCLUSIONS: To our knowledge, this is the first example of a theoretical model that gives a satisfactory relationship between calculated molecular properties and epithelial permeability to peptides by accounting for both the hydrogen bonding capacity and the hydrophobicity of the investigated molecule. This model may be used to differentiate poorly absorbed oligopeptide drugs at an early stage of the drug discovery process.

Biological Transport↗
PubMed1993

Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments.

New data on the permeabilities of hydrophilic markers in two commonly used in vitro models, i.e., excised intestinal segments from the rat and monolayers of Caco-2 cells, are presented. The results are compared to human in vivo data. Two groups of hydrophilic marker molecules were tested: (1) monodisperse polyethylene glycols of molecular weights ranging from 194 to 502 g/mol and (2) a heterogeneous group of molecules consisting of urea, creatinine, erythritol, and mannitol (60-182 g/mol). The permeabilities of the marker molecules showed a nonlinear dependence on the molecular weight and decreased in the order rat ileum > rat colon > Caco-2 cells. Surprisingly, the polyethylene glycols permeated more easily than the other marker molecules, indicating that characteristics other than molecular weight, e.g., the flexibility of the structure, may also be important for permeation through the membrane. Comparisons with the published permeability profiles of polyethylene glycols in human intestinal segments in vivo (i.e., calculated permeability coefficients as a function of molecular weight) indicate that the human intestine is more permeable than the in vitro models. However, the permeability profiles of the corresponding segments in the human intestine and the in vitro models were comparable. Thus, good correlations were established between permeabilities of the human ileum and rat ileum and between those of human colon, rat colon, and the Caco-2 cells. We conclude that the paracellular absorption in humans can be studied mechanistically in these in vitro models.

Animals↗
PubMed2000

Mechanisms of transport and structure-permeability relationship of sulfasalazine and its analogs in Caco-2 cell monolayers.

PURPOSE: To investigate the mechanisms involved in transport of sulfasalazine in Caco-2 cells. METHODS: Permeability coefficients of sulfasalazine and its analogs across Caco-2 cell monolayers were measured as a function of direction of transport, energy and concentration dependence, and in the presence of inhibitors of various cellular efflux pumps and transporters. RESULTS: Permeability coefficients of sulfasalazine across Caco-2 cell monolayers were approximately 342-, 261-, and 176-fold higher from basolateral to apical direction (BL-->AP) than from apical to basolateral direction (AP-->BL) at 100, 200, and 500 microM, respectively. Carrier permeability coefficient, non-saturable membrane permeability coefficient, and Michaelis constant were estimated to be 1.4x10(-5) cm/s, 1.9x10(-8) cm/s, and 369 microM, respectively. The efflux of sulfasalazine was completely blocked at 4 degrees C and in the presence of an uncoupler of oxidative phosphorylation. Using cellular efflux inhibitors, the permeability of sulfasalazine was shown to depend on multidrug resistance-associated protein and anion sensitive transport mechanisms. Structure-permeability studies showed that the affinity of sulfasalazine for the cellular efflux pumps and transporters in Caco-2 cells depended strongly on the carboxylic acid functional group. CONCLUSIONS: The permeability of sulfasalazine across Caco-2 cell monolayer is very low due to its strong interaction with multiple cellular efflux pumps and transporters. This may partially explain its low absorption in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗