Compartmental Modeling of Transdermal Iontophoretic Transport: I. In Vitro Model Derivation and Application

PURPOSE: The objective of this study was to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vitro. METHODS: Two structurally different compartmental models describing the in vitro transport during iontophoresis and one compartmental model describing the in vitro transport in post-iontophoretic period are proposed. These models are based on the mass transfer from the donor compartment to the acceptor compartment via the skin as an intermediate compartment. In these models, transdermal iontophoretic transport is characterized by 5 parameters: 1) kinetic lag time (tL), 2) steady-state flux during iontophoresis (Jss), 3) skin release rate constant (K(R)), 4) the first-order rate constant of the iontophoretic driving force from the skin to the acceptor compartment (I1), and 5) passive flux in the post-iontophoretic period (Jpas). The developed models were applied to data on the iontophoretic transport in human stratum corneum in vitro of R-apomorphine after pretreatment with phosphate buffered saline pH 7.4 (PBS) and after pretreatment with surfactant (SFC), as well as the iontophoretic transport of 0.5 mg ml(-1) rotigotine at pH 5 (RTG). RESULTS: All of the proposed models could be fitted to the transport data of PBS, SFC, and RTG groups both during the iontophoresis and in the post-iontophoretic period. The incorporation of parameter I1 failed to improve the fitting performance of the model. This might indicate a negligible contribution of iontophoretic driving force to the mass transfer in the direction from the skin to the acceptor compartment, although it plays an important role in loading the skin with the drug. The estimated values of Jss of PBS, SFC, and RTG were identical (p > 0.05) to the values obtained with the diffusion lag time method. Moreover, time required to achieve steady-state flux can be estimated based on the parameter tL and the reciprocal value of parameter K(R). In addition, accumulation of drug molecules in the skin is reflected in a reduction of the value of the K(R) parameter. CONCLUSIONS: The developed in vitro models demonstrated their strength and consistency to describe the drug transport during and post-iontophoresis.     

<Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">in Vivo</Emphasis> Correlation of Transdermal Naltrexone Prodrugs in Hairless Guinea Pigs

Purpose The purpose of this investigation was to evaluate the in vitro and in vivo percutaneous absorption of the following prodrugs of naltrexone (NTX): 2-ethylbutyryl-3-O-ester-NTX (ETBUT-ester), methyl-3-O-carbonate-NTX (ME-carbonate), ethyl-3-O-carbamate-NTX (ET-carbamate), and N,N-dimethyl-3-O-carbamate-NTX (DME-carbamate) in hairless guinea pigs.Methods In vitro fluxes of NTX and its prodrugs through guinea pig skin were determined using a flow-through diffusion cell system. The pharmacokinetics of NTX prodrugs were determined after topical application of transdermal patches in guinea pigs.Results All the prodrugs hydrolyzed to NTX on passing through the skin, and ME-carbonate provided the highest NTX flux and had the highest apparent permeability coefficient (K_p). ME-carbonate and ET-carbamate underwent the highest extent of bioconversion to NTX upon passing through the skin as compared to ETBUT-ester and DME-carbamate. The results of the in vivo studies indicated that a significant amount of NTX was delivered after the application of transdermal patches of NTX prodrugs. A mean steady-state plasma concentration of 7.1 ng/ml was obtained after the application of transdermal patches of ME-carbonate. A good correlation was obtained between the in vitro and in vivo results.Conclusions The results of the in vivo studies indicated that the ME-carbonate prodrug of NTX was the most promising drug candidate for transdermal delivery.     

Magnetic Nanoparticles Enhance Adenovirus Transduction <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis>

Purpose  

Adenoviruses are among the most powerful gene delivery systems. Even if they present low potential for oncogenesis, there is still a need for minimizing widespread delivery to avoid deleterious reactions. In this study, we investigated Magnetofection efficiency to concentrate and guide vectors for an improved targeted delivery.     

Transdermal Iontophoretic Delivery of Vapreotide Acetate AcrossPorcine Skin <Emphasis Type="BoldItalic">in Vitro</Emphasis>

Purpose The purpose of this study was to evaluate the feasibility of delivering vapreotide, a somatostatin analogue, by transdermal iontophoresis.Methods In vitro experiments were conducted using dermatomed porcine ear skin and heat-separated epidermis. In addition to quantifying vapreotide transport into and across the skin, the effect of peptide delivery on skin permselectivity was also measured. The influence of (1) current density, (2) pre- and post-treatment of the skin, (3) competitive ions, and (4) inclusion of albumin in the receptor on vapreotide delivery were investigated.Results Epidermis proved to be a better model than dermatomed skin for vapreotide transport studies. Despite the susceptibility of vapreotide to enzymatic degradation, a flux of 1.7 μg/cm² per hour was achieved after 7 h of constant current iontophoresis (0.15 mA/cm²). Post-iontophoretic extraction revealed that, depending on the experimental conditions, 80–300 μg of peptide were bound to the skin. Vapreotide was found to interact with the skin and displayed a current-dependent inhibition of electroosmosis. However, neither the pre-treatment strategies to saturate the putative binding sites nor the post-treatment protocols to displace the bound peptide were effective.Conclusion Based on the observed transport rate of vapreotide across porcine epidermis and its clinical pharmacokinetics, therapeutic concentrations should be achievable using a 15-cm² patch.     

Gender-Dependent Pharmacokinetics of Veratramine in Rats: <Emphasis Type="Italic">In Vivo</Emphasis> and <Emphasis Type="Italic">In Vitro</Emphasis> Evidence

Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and anti-hypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant male-predominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.     

Population <Emphasis Type="Italic">In Vitro</Emphasis>-<Emphasis Type="Italic">In Vivo</Emphasis> Correlation Model for Pramipexole Slow-Release Oral Formulations

Purpose  

To establish an in vitro-in vivo level A correlation (IVIVC) for pramipexole slow-release formulations.     

Michaelis-Menten from an <Emphasis Type="Italic">In Vivo</Emphasis> Perspective: Open <Emphasis Type="Italic">Versus</Emphasis> Closed Systems

After a century of applications of the seminal Michaelis-Menten equation since its advent it is timely to scrutinise its principal parts from an in vivo point of view. Thus, the Michaelis-Menten system was revisited in which enzymatic turnover, i.e. synthesis and elimination was incorporated. To the best of our knowledge, previous studies of the Michaelis-Menten system have been mainly based on the assumption that the total pool of enzyme, free and bound, is constant. However, in fact this may not always be the case, particularly for chronic indications. Chronic (periodic) administration of drugs is often related to induction or inhibition of enzymatic processes and even changes in the free enzymatic load per se. This may account for the fact that translation of in vitro metabolism data have shown to give systematic deviations from experimental in vivo data. Interspecies extrapolations of metabolic data are often challenged by poor predictability due to insufficient power of applied functions and methods. By incorporating enzyme turnover, a more mechanistic expression of substrate, free enzyme and substrate-enzyme complex concentrations is derived. In particular, it is shown that whereas in closed systems there is a threshold for chronic dosing beyond which the substrate concentration keeps rising, in open systems involving enzyme turnover this is no longer the case. However, in the presence of slow enzyme turnover, after an initial period of adjustment which may be quite long, the relation between substrate concentration and dose rate reduces to a linear expression. This new open framework is also applicable to transporter systems.     

Transmucosal delivery of domperidone from bilayered buccal patches: <Emphasis Type="Italic">In Vitro,Ex Vivo</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> characterization

Bilayered mucoadhesive buccal patches for systemic administration of domperidone (DOM), a dopamine-receptor (D₂) antagonist, were developed using hydroxy propyl methyl cellulose and PVPK30 as a primary layer and Eudragit RLPO and PEO as a secondary layer. Ex vivo drug permeation through porcine buccal membrane was performed. Bilayered buccal patches were developed by solvent casting technique and evaluated for in vitro drug release, moisture absorption, mechanical properties, surface pH, in vitro bioadhesion, in vivo residence time and ex vivo permeation of DOM through porcine buccal membrane from a bilayered buccal patch. Formulation DB4 was associated with 99.5% drug release with a higuchi model release profile and 53.9% of the drug had permeated in 6 h, with a flux of 0.492 mg/h/cm² through porcine buccal membrane. DB4 showed 5.58 N and 3.28 mJ peak detachment force and work of adhesion, respectively. The physicochemical interactions between DOM and the polymer were investigated by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) Spectroscopy. DSC and FTIR studies revealed no interaction between drug and polymer. Stability studies for optimized patch DB4 was carried out at 40°C/75% relative humidity. The formulations were found to be stable over a period of 3 months with respect to drug content, in vitro release and ex vivo permeation through porcine buccal membrane. The results indicate that suitable bilayered mucoadhesive buccal patches with desired permeability could be prepared.     

Paclitaxel-Loaded,Folic-Acid-Targeted and TAT-Peptide-Conjugated Polymeric Liposomes: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Objective  

Folic acid and TAT peptide were conjugated on the octadecyl-quaternized, lysine-modified chitosan-cholesterol polymeric liposomes (FA-TATp-PLs) to investigate their potential feasibility for tumor-targeted drug delivery.     

<Emphasis Type="Italic">In Vitro</Emphasis> Metabolism of 5-ALA Esters Derivatives in Hairless Mice Skin Homogenate and <Emphasis Type="Italic">in Vivo</Emphasis> PpIX Accumulation Studies

No HeadingPurpose. In topical photodynamic therapy, 5-ALA and its esters are enzymatically converted in the endogenous photosensitizing compounds such as, for example, protoporphyrin IX (PpIX). In order to elucidate in more detail their enzymatic fate, we have determined in vitro the enzymatic degradation of methyl, butyl, hexyl, and octyl-5-ALA ester derivatives in skin homogenate. Furthermore, in vivo porphyrin accumulation was measured in healthy hairless mice skins.Methods. Hairless mouse skins were homogenized in isotonic phosphate buffer pH 7.4. 5-ALA esters were added, and aliquots were colleted for HPLC-fluorimetric determinations of remaining content of 5-ALA esters. Furthermore, oil-in-water emulsions containing esters were topically applied to mice skin for 6 h, and the amount of accumulated PpIX in the treated areas was determined by quantitative extraction and confocal fluorescence microscopy.Results. The enzymatic degradation of esters follows pseudo first-order kinetics. The octyl ester had the largest rate constant for enzymatic degradation, followed by hexyl-, butyl-, and methyl-ALA. The long-chained 5-ALA esters, butyl-, hexyl-, and octyl ester, induced significantly more porphyrins than 5-ALA and 5-ALA methyl ester as shown by confocal microscopy and quantitative extraction studies.Conclusions. 5-ALA derivatives differ widely with respect to their enzymatic degradation. The presence of alkyl chains in 5-ALA esters significantly influences the in vitro enzymatic metabolism and the in vivo PpIX formation in healthy hairless mice skins.     

A Semi-mechanistic Modeling Strategy to Link <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Drug Release for Modified Release Formulations

Purpose  

To develop a semi-mechanistic model linking in vitro to in vivo drug release.     

Key to Opening Kidney for <Emphasis Type="Italic">In Vitro-In Vivo</Emphasis> Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and <Emphasis Type="Italic">In Vitro-In Vivo</Emphasis> Extrapolation

It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th–29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drug-drug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22

In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 μM FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 μM was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after β-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the same metabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after β-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake.     

Radioactive Holmium Acetylacetonate Microspheres for Interstitial Microbrachytherapy: An <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Stability Study

Purpose  

The clinical application of holmium acetylacetonate microspheres (HoAcAcMS) for the intratumoral radionuclide treatment of solid malignancies requires a thorough understanding of their stability. Therefore, an in vitro and an in vivo stability study with HoAcAcMS was conducted.     

Bioadhesive Films Containing Benzocaine: Correlation Between <Emphasis Type="Italic">In Vitro</Emphasis> Permeation and <Emphasis Type="Italic">In Vivo</Emphasis> Local Anesthetic Effect

Purpose  

The aim of this work was to develop anesthetic bioadhesive films containing benzocaine and study their in vitro skin permeation and in vivo performance, in comparison with commercial formulations.     

Examining the Use of a Mechanistic Model to Generate an <Emphasis Type="Italic">In Vivo</Emphasis>/<Emphasis Type="Italic">In Vitro</Emphasis> Correlation: Journey Through a Thought Process

The attention and interest in establishing in vivo/in vitro correlations (IVIVCs) is grounded in its tremendous utility as a prognostic tool. It can be used to support formulation optimization, predict in vivo drug exposure across a potential patient population, select a biologically relevant in vitro dissolution test condition, and support the use of in vitro dissolution data as a surrogate for in vivo bioequivalence trials. The pharmacological and statistical implications of this correlation are linked to the method by which the IVIVC was determined and to the assumptions and optimization approaches integrated into the estimation procedure. Using previously published data generated in normal healthy volunteers, an IVIVC for metoprolol was established using a mechanistic modeling approach. Within that framework, we explored the consequences of (1) our method of fitting a single Weibull function to the in vivo dissolution, (2) our selection of weighting scheme and optimization approaches, (3) the impact of applying a fixed versus fitted gastric emptying time, and 4) the importance of factoring population variability into our IVIVC estimation and profile reconvolution. We identified those factors found to be critical in terms of their influence on the accuracy of our predicted systemic metoprolol concentration-time profiles. We considered the strengths and weaknesses of our approach and discussed how the results of this study may impact efforts to generate IVIVCs with compounds presenting physicochemical characteristics different from that of metoprolol.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Effects of Water Extract of White Cocoa Tea (<Emphasis Type="Italic">Camellia ptilophylla</Emphasis>) Against Human Prostate Cancer

Purpose  

We evaluated the chemotherapeutic effect of water extract of white cocoa tea (WCTE) against human prostate cancer (PCa) in vitro and in vivo.     

A Dual-Biotic System for the Concurrent Delivery of Antibiotics and Probiotics: <Emphasis Type="Italic">In Vitro</Emphasis>, <Emphasis Type="Italic">Ex Vivo</Emphasis>, <Emphasis Type="Italic">In Vivo and In Silico</Emphasis> Evaluation and Correlation

Purpose

A delayed release bio-polymeric Dual-Biotic system has been extensively evaluated in this study to overcome the therapeutic issue of probiotic killing due to incorrect administration with the antibiotic.

Methods

In vitro and ex vivo release and characterization studies have been undertaken on the Dual-Biotic system. In vivo analyses utilizing a Large White pig model were also performed with commercial products used as a comparison. Intestinal fluid for probiotic quantification was aspirated using a surgically implanted intestinal cannula with Lactobacillus acidophilus cell counts determined through luminescence and inoculation onto Lactobacilli-specific agar. Plasma amoxicillin concentrations were determined through Ultra-Performance Liquid Chromatography. The reactional profile and crosslinking mechanism of ovalbumin and genipin was elucidated using molecular mechanic energy relationships in a vacuum system by exploring the spatial disposition of different concentrations of genipin with respect to ovalbumin with ovalbumin/genipin ratios of 1:1, 1:5 and 1:10.

Results

In vivo evaluation of the Dual-Biotic system detailed maximum Lactobacillus viability (~455% baseline viability) 6 h after oral administration. Concurrent administration of the commercial products revealed a 75% decrease in bacterial viability when compared to the controls analyzed. A level A in vitro-in vivo correlation was also established with 96.9% predictability of amoxicillin release ascertained. The computational results achieved corroborated well with the experimental findings and physicochemical data.

Conclusions

Evaluation and correlation of the Dual-Biotic system has detailed the success of the formulation for the concurrent delivery of an antibiotic and probiotic.

     

Stereoselective Taurine Conjugation of (<Emphasis Type="Italic">R</Emphasis>)-Benoxaprofen Enantiomer in Rats: <Emphasis Type="Italic">In Vivo</Emphasis> and <Emphasis Type="Italic">in Vitro</Emphasis> Studies Using Rat Hepatic Mitochondria and Microsomes

No HeadingPurpose. Identify (R)-BOP-T in rat bile after administration of (R)-BOT over a 12 h period.Methods. Each benoxaprofen (BOP) enantiomer was administered i.v. to bile duct-cannulated rats at a dose of 5 mg/kg. The optical isomers of BOP and its metabolites in plasma, urine, and bile were quantified using a chiral HPLC column. The amounts of BOP glucuronide (BOP-G), BOP taurine conjugate (BOP-T), and BOP enantiomers excreted into the bile over 12 h after administration of (R)-BOP were as follows: (R)-BOP-G and (S)-BOP-G, 2.1 ± 0.5 and 6.2 ± 1.4% of the dose; (R)-BOP-T and (S)-BOP-T, 5.6 ± 1.8 and 0.7 ± 0.3% of the dose; (R)-BOP and (S)-BOP, 0.7 ± 0.1 and 1.7 ± 0.2% of the dose, respectively, whereas after (S)-BOP administration, (S)-BOP-G and (S)-BOP were mainly excreted into the bile (14.3 ± 1.8 and 3.0 ± 0.4% of the dose, respectively). Only after (R)-BOP administration was the taurine conjugate of BOP found in the bile, and the configuration was R. BOP-T could not be found in the bile after (S)-BOP administration. To investigate the stereoselectivity of the conjugation enzymes responsible for BOP-T formation, in vitro studies were performed using rat hepatic organelles.Results. When (R)-BOP was used as a substrate, rat hepatic mitochondrial and microsomal fractions exhibited stereoselective BOP-T formation activity, with microsomal activity approximately 3.0 times greater than that of the mitochondria. That of (S)-BOP was approximately 2.1. Mean (R)/(S) ratios of BOP enantiomer for BOP-T formation in the mitochondrial and microsomal incubations were approximately 1.7 and 2.4, respectively.Conclusion. Although in the in vivo studies, only (R)-BOP-T originated from (R)-BOP was found in the bile, the configuration of BOP-T formed by the incubations of (R)-BOP or (S)-BOP with rat hepatic mitochondria or microsomes was S for both.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">ex Vivo</Emphasis> Intestinal Tissue Models to Measure Mucoadhesion of Poly (Methacrylate) and <Emphasis Type="Italic">N</Emphasis>-Trimethylated Chitosan Polymers

No HeadingPurpose. The adhesion of a range of polymers based on poly(2-(dimethylamino-ethyl) methacrylate (pDMAEMA) was assessed using human mucus-secreting and non mucus-secreting intestinal cell monolayers, HT29-MTX-E12 (E12) and HT29 monolayers, as well as excised non-everted intestinal sacs from rats. Differentiation of mucoadhesion from bioadhesion was achieved by pre-treatment with the mucolytic agent, N-acetyl cysteine (NAC). Adherence of pDMAEMA polymers was compared to that obtained with the mucoadhesive, N-trimethylated chitosan (TMC).Methods. The quantity of adherent coumarin 343-conjugated polymers to HT29, E12, and intestinal sacs was measured by fluorescence. Confocal laser scanning microscopy (CLSM), light microscopy, and fluorescent microscopy were used to provide direct evidence. Measurements of transepithelial electrical resistance (TEER), permeability to FITC-dextran 4000 (FD-4), and the release of lactate dehydrogenase (LDH) were used to assess potential cytotoxicity of polymers.Results. Adherence of unquaternized and of 10%, 24%, and 32% methyl iodide-quaternized pDMAEMA polymers was measured in E12, HT29, and sacs. All pDMAEMA polymers showed significantly higher levels of adhesion to mucus (mucoadhesion) than to epithelium (bioadhesion). Colocalization of pDMAEMA with mucus was confirmed in E12 by microscopy. TMC showed equally high levels of mucoadhesion as unquaternized and 24% quaternized pDMAEMA, but displayed higher levels of bioadhesion. pDMAEMA-based polymers demonstrated lower levels of adherence to E12 and rat sacs in the presence of NAC, whereas adherence of TMC was unchanged. pDMAEMA significantly decreased the permeability of FD-4 across E12 monolayers and sacs and was less cytotoxic in E12 than in HT29. In contrast, TMC increased the permeability of FD-4 across E12 and sacs and was less cytotoxic in E12 than in HT29.Conclusions. Human mucus–producing E12 monolayers can be used to assess polymer mucoadhesion and give similar data to isolated rat intestinal sacs. pDMAEMA displayed similar levels of mucoadhesion and lower levels of bioadhesion than a chitosan derivative and it was not cytotoxic. pDMAEMA decreased FD-4 flux in the presence of mucus, whereas TMC increased it. The combination of mucus and methacrylate polymers appears to increase barrier function of the apical membrane.