Drug Absorption Studies

Ehrhardt, Carsten; Kim, Kwang‐Jin

doi:10.1007/978-0-387-74901-3

Cited by 37 publications

(3 citation statements)

References 593 publications

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“…The need for robust in vitro test systems of the nasal cavity has been driven mostly by the necessity to successfully deliver medications via the nasal route, such as the intranasal delivery of vaccines against respiratory infections (Kim, 2008). The nasal mucosa protects the sensitive lower airway tissues against harmful agents in the environment.…”

Section: R4f Smoke and Ths22 Aerosol Exposure And Endpoint Generationmentioning

confidence: 99%

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Iskandar

Mathis

Martin

et al. 2017

ALTEX

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ratory animals -to reduce the number of animals, to refine the design of procedures such that pain and distress are minimized, and to replace animal models with alternative methods and lower organisms when possible (Doke and Dhawale, 2015). In this regard, the capability to preserve human respiratory cells in culture provides a tool not only to generate mechanistic data, but also to improve the predicted effects of exposure hazard through inhalation in humans. An emphasis on assessment studies using human-derived in vitro culture systems will reduce the problems that are inherent to interspecies translatability (Manuppello and Sullivan, 2015).In vitro toxicology approaches have evolved from focusing on the molecular changes within a cell to understanding the toxicity-related mechanisms (cell-cell interactions) in models IntroductionMechanistic investigation of the impact of exposure on the lower airway remains challenging because access to lung tissues is limited. Although biopsy samples can be obtained from patients/donors for mechanistic studies of exposure-induced injury, a biopsy procedure is invasive and there are related ethical concerns (Peppercorn, 2013). Alternatively, animal studies allow the collection of biological samples from various animal models of human diseases. However, biological responses can vary among animal species, and findings obtained from animal studies may not apply to humans. Alternatives to animal testing have been proposed to overcome these drawbacks, including the 3Rs strategy -reduction, refinement, and replacement of labo- Research SummaryIn vitro toxicology approaches have evolved from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus, the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. Aligned with 3Rs strategy, this study aimed to explore the relevance of a human 3-D nasal culture model to assess the toxicological impact of aerosols generated from a candidate modified risk tobacco product (cMRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F. A series of experimental repetitions, where multiple concentrations of THS2.2 aerosol and 3R4F smoke were applied, were conducted to obtain reproducible measurements to understand the cellular/molecular changes that occur following exposure. In agreement with "Toxicity Testing in the 21 st Century -a Vision and a Strategy", this study implemented a systems toxicology approach and found that for all tested concentrations the impa...

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Section: R4f Smoke and Ths22 Aerosol Exposure And Endpoint Generationmentioning

confidence: 99%

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Iskandar

Mathis

Martin

et al. 2017

ALTEX

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“…In the past two decades, cell-based models of different biological barriers (e.g., intestine, skin) have been developed to better predict drug absorption and, at the same time, to reduce the use of experimental animals, which is ethically questioned [9]. In this context, the Caco-2 cell line monolayer became extremely popular as an in vitro model of the intestinal epithelium due to its ability to express most morphological and functional characteristics of absorptive small intestine cells, including tight junctions (TJs) and efflux pumps of the ATP-binding cassette superfamily [8,10], presenting good correlation for the estimation of oral drug absorption in humans [11]. However, the Caco-2 cell line also displays some shortcomings.…”

Section: Introductionmentioning

confidence: 99%

Permeability of Novel Chitosan-g-Poly(Methyl Methacrylate) Amphiphilic Nanoparticles in a Model of Small Intestine In Vitro

et al. 2018

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Engineering of drug nanocarriers combining fine-tuned mucoadhesive/mucopenetrating properties is currently being investigated to ensure more efficient mucosal drug delivery. Aiming to improve the transmucosal delivery of hydrophobic drugs, we designed a novel nanogel produced by the self-assembly of amphiphilic chitosan graft copolymers ionotropically crosslinked with sodium tripolyphosphate. In this work, we synthesized, for the first time, chitosan-g-poly(methyl methacrylate) nanoparticles thiolated by the conjugation of N-acetyl cysteine. First, we confirmed that both non-crosslinked and crosslinked nanoparticles in the 0.05–0.1% w/v concentration range display very good cell compatibility in two cell lines that are relevant to oral delivery, Caco-2 cells that mimic the intestinal epithelium and HT29-MTX cells that are a model of mucin-producing goblet cells. Then, we evaluated the effect of crosslinking, nanoparticle concentration, and thiolation on the permeability in vitro utilizing monolayers of (i) Caco-2 and (ii) Caco-2:HT29-MTX cells (9:1 cell number ratio). Results confirmed that the ability of the nanoparticles to cross Caco-2 monolayer was affected by the crosslinking. In addition, thiolated nanoparticles interact more strongly with mucin, resulting in a decrease of the apparent permeability coefficient (Papp) compared to the pristine nanoparticles. Moreover, for all the nanoparticles, higher concentration resulted in lower Papp, suggesting that the transport pathways can undergo saturation.

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“…Depending on the administration route of a given compound and its target milieu in the biological environment, an ideal candidate for a drug must have lipophilicity allowing for penetration through relevant barriers. Thus, for example, a drug targeting the central nervous system should ideally have a logP value around 2 [38] while for oral and intestinal absorption the ideal value is 1.35-1.8 [39]. Therefore, LogP helps to predict the likely transport of a compound around the body.…”

Section: Plos Onementioning

confidence: 99%

Correlations between molecular structure and biological activity in "logical series" of dietary chromone derivatives

et al. 2020

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The research was conducted in the "logical series" of seven ligands: chromone, flavone, 3hydroxyflavone, 3,7-dihydroxyflavone, galangin, kaempferol and quercetin. Each subsequent ligand differs from the previous one, among others by an additional hydroxyl group. The studied chromone derivatives are plant secondary metabolites which play an important role in growth, reproduction, and resistance to pathogens. They are important food ingredients with valuable pro-health properties. The studies of the relationships between their molecular structure and biological activity facilitate searching for new chemical compounds with important biological properties not by trial and error, but concerning the impact of specific changes in their structure on the compound properties. Therefore several pectroscopic methods (FT-IR, FT-Raman, 1 H and 13 C NMR) were applied to study the molecular structure of the compounds in the series. Moreover the quantum-chemical calculations at B3LYP/6-311++G** were performed to obtained the theoretical NMR spectra, NBO atomic charge, global reactivity descriptors and thermodynamic parameters. The antioxidant activity of the compounds was tested in the DPPH and FRAP assays and the mechanism of antioxidant activity was discussed based on the results on theoretical calculations. The cytotoxicity of the ligands toward human epithelial colorectal adenocarcinoma Caco2 cells was estimated and correlated with the lipophilicity of the compounds. The principal component analyses (PCA) and hierarchical cluster analysis were used to study the dependency between the molecular structure of ligands and their biological activity. The experimental data were related to the theoretical ones. The found regular changes in physicochemical properties correlated well with the systematic changes in antioxidant and biological properties.

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Drug Absorption Studies

Cited by 37 publications

References 593 publications

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Permeability of Novel Chitosan-g-Poly(Methyl Methacrylate) Amphiphilic Nanoparticles in a Model of Small Intestine In Vitro

Correlations between molecular structure and biological activity in "logical series" of dietary chromone derivatives

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