Modeling the In Vivo Case with In Vitro Nanotoxicity Data

2008 ◽  
Vol 27 (5) ◽  
pp. 359-367 ◽  
Author(s):  
Michael L. Shelley ◽  
Andrew J. Wagner ◽  
Saber M. Hussain ◽  
Charles Bleckmann
Keyword(s):  
Chemical Exposure ◽  
Pbpk Modeling ◽  
In Vivo Studies ◽  
Cell Dynamics ◽  
Nanoparticle Exposure ◽  
Pbpk Models ◽  
In Vitro Effects ◽  
Single Cell Type

As more in vitro nanotoxicity data appear in the literature, these findings must be translated to in vivo effects to define nanoparticle exposure risk. Physiologically based pharmacokinetic (PBPK) modeling has played a significant role in guiding and validating in vivo studies for molecular chemical exposure and can develop as a significant tool in guiding similar nanotoxicity studies. This study models the population dynamics of a single cell type within a specific tissue. It is the first attempt to model the in vitro effects of a nanoparticle exposure, in this case aluminum (80 nm) and its impact on a population of rat alveolar macrophages ( Wagner et al. 2007 , J. Phys. Chem. B 111:7353–7359). The model demonstrates how in vitro data can be used within a simulation setting of in vivo cell dynamics and suggests that PBPK models should be developed quickly to interpret nanotoxicity data, guide in vivo study design, and accelerate nanoparticle risk assessment.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

Abstract 17071: Cell Communication Inference in Macrophages

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nika Taghdiri ◽  
Kevin R King ◽  
David Calcagno ◽  
Zhenxing Fu ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Image Analysis ◽  
Analytical Methods ◽  
Cell Injury ◽  
Diffusion Mechanism ◽  
Cell Communication ◽  
In Vivo Studies ◽  
Cell Dynamics ◽  
Calcium Indicator

Introduction: Tissue macrophages play diverse roles in the cardiovascular system during health and disease. They have diverse functions within tissues, but our understanding of their dynamics is limited because most macrophage characterization assays are destructive and have low temporal resolution. We asked whether these cells are dynamic and interconnected. Methods: Here, we describe experimental and analytical methods for measuring cell dynamics and inferring communication between cells in vitro and in vivo. We created a mouse (Csf1r-Cre x GCaMP5) expressing the Cre-inducible genetically encoded calcium indicator GCaMP5 under the regulation of the innate immune promoter, Csf1r, to non-destructively quantify high-frequency cell dynamics and differentiated them in culture using m-CSF. We developed custom image analysis routines and parameterization strategies for classifying calcium responses. Results: Our studies revealed that calcium reporter BMDMs display minimal fluctuations at baseline but exhibit a dynamic response to immunogenic DNA sensing. DNA-induced isolated cell injury and death, which precipitated cell communication that spread with a velocity of [9μm/s], consistent with an extracellular diffusion mechanism. We developed quantitative image analysis methods that corrected for random calcium fluctuations and identified statistically significant areas of correlated calcium changes suggestive of communication. An analytical pipeline enabled quantification of calcium spike dynamics and correlations of dynamic calcium profiles of single cell sharing a local microenvironment. This resulted in an “improbable synchrony” metric that allowed localization of communication in time and space. We adapted the pipeline for in vivo studies and tested them in a dorsal window chamber model using intravital microscopy. At 2Hz sampling frequency, we identified 27 potential communication events as they responded to complex microenvironmental cues in vivo. Conclusion: The experimental and analytical methods for inferring cell communication provide a new quantitative toolkit for investigating known as-yet undiscovered cell communication pathways.

scholarly journals Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Jane C. Caldwell ◽  
Marina V. Evans ◽  
Kannan Krishnan
Keyword(s):  
Risk Assessment ◽  
Model Development ◽  
Pbpk Modeling ◽  
Human Populations ◽  
Pbpk Models ◽  
Modeling Process ◽  
Physiologically Based Pharmacokinetic ◽  
State Of The Science

Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation betweenin vitroexposures,in vivophysiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process.

The myelotoxicity of chloramphenicol: in vitro and in vivo studies: I. In vitro effects on cells in culture

1997 ◽  
Vol 16 (10) ◽  
pp. 570-576 ◽  
Author(s):  
DE Holt ◽  
TA Ryder ◽  
A. Fairbairn ◽  
R. Hurley ◽  
D. Harvey
Keyword(s):  
Progenitor Cells ◽  
Aplastic Anaemia ◽  
Monkey Kidney ◽  
In Vivo Studies ◽  
Patient Treatment ◽  
Morphological Effect ◽  
Dividing Cells ◽  
In Vitro Effects

1 Chloramphenicol is used extensively in non-industria lized countries for the treatment of life-threatening infections because it is cheap and effective, despite its known hemotoxicity and linkage to fatal aplastic anaemia. It is important to define the mechanism of toxicity so that means can be devised to ameliorate the toxic effects in order to produce safer usage. 2 Chloramphenicol, at concentrations from 5 mM to 2 mM initiated apoptosis in dividing cells from a monkey kidney-derived cell line and in haematopoie tic progenitor cells from human neonatal cord blood. 3 Growth of progenitor cells was suppressed at concen trations of chloramphenicol which would be consid ered less than therapeutic during patient treatment. 4 These effects could be ameliorated in progenitor cells by co-culture with the antioxidant mercaptoethyla mine and in monkey kidney cells by co-culture with vitamin C. 5 This is the first report of apoptosis in chloramphenicol toxicity and suggests a possible link between a metabolic event i.e. the production of free radicals; a morphological effect, apoptosis; and a clinical effect, bone marrow suppression and aplastic anaemia.

scholarly journals The Effect of Stromal-Derived Factor 1α on Osteoinduction Properties of Porous β-Tricalcium Phosphate Bioceramics

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Fangchun Jin ◽  
Qixun Cai ◽  
Wei Wang ◽  
Xiaohui Fan ◽  
Xiao Lu ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Tricalcium Phosphate ◽  
Tissue Repair ◽  
In Vivo Studies ◽  
New Bone Formation ◽  
Defect Model ◽  
Rabbit Bone ◽  
In Vitro Effects

β-Tricalcium phosphate (TCP) is a type of bioceramic material which is commonly used for hard tissue repair and famous of its remarkable biocompatibility and osteoconductivity with similar composition to natural bone. However, TCP lacks osteoindcutive properties. Stromal-derived factor 1α (SDF-1α) can promote bone regeneration with excellent osteoinduction effect. In this study, SDF-1α was loaded into TCP to investigate the in vitro effects of SDF-1α on the osteoinductive properties of TCP. In vitro studies showed that SDF-1α/TCP scaffold significantly stimulated the expression of osteopontin and osteocalcin. As to the in vivo studies, the rabbit bone defect model showed that SDF-1α stimulated more new bone formation. In conclusion, SDF-1α/TCP bioceramic scaffolds could further promote bone regeneration compared to pure TCP bioceramics.

scholarly journals Mass Spectrometry-Based Zebrafish Toxicometabolomics: A Review of Analytical and Data Quality Challenges

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 635
Author(s):  
Katyeny Manuela da Silva ◽  
Elias Iturrospe ◽  
Chloe Bars ◽  
Dries Knapen ◽  
Steven Van Cruchten ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Chemical Exposure ◽  
Research Field ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Special Focus ◽  
Zebrafish Model ◽  
Wide Range

Metabolomics has achieved great progress over the last 20 years, and it is currently considered a mature research field. As a result, the number of applications in toxicology, biomarker, and drug discovery has also increased. Toxicometabolomics has emerged as a powerful strategy to provide complementary information to study molecular-level toxic effects, which can be combined with a wide range of toxicological assessments and models. The zebrafish model has gained importance in recent decades as a bridging tool between in vitro assays and mammalian in vivo studies in the field of toxicology. Furthermore, as this vertebrate model is a low-cost system and features highly conserved metabolic pathways found in humans and mammalian models, it is a promising tool for toxicometabolomics. This short review aims to introduce zebrafish researchers interested in understanding the effects of chemical exposure using metabolomics to the challenges and possibilities of the field, with a special focus on toxicometabolomics-based mass spectrometry. The overall goal is to provide insights into analytical strategies to generate and identify high-quality metabolomic experiments focusing on quality management systems (QMS) and the importance of data reporting and sharing.

scholarly journals The Epithelial Barrier Model Shows That the Properties of VSL#3 Depend from Where it is Manufactured

2019 ◽  
Vol 19 (2) ◽  
pp. 199-206 ◽  
Author(s):  
Paola Palumbo ◽  
Francesca Lombardi ◽  
Maria Grazia Cifone ◽  
Benedetta Cinque
Keyword(s):  
Heat Stress ◽  
In Vivo Studies ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Pre Treatment ◽  
In Vitro Effects ◽  
Opposing Effects ◽  
Barrier Model

Background: VSL#3 has been extensively investigated and is currently recommended for the prevention and treatment of chronic pouchitis and ulcerative colitis. Nonetheless, in vitro and in vivo studies have recently shown variability in the VSL#3 efficacy often attributed to the manufacturing process. Objective: The aim was to comparatively study the in vitro effects of two VSL#3 preparations produced in different sites (named US- and Italy-made VSL#3) on CaCo-2 epithelial barrier model in terms of trans-epithelial electrical resistance (TEER), dextran flux and expression of Tight Junctions (TJ) proteins i.e. zonulin-1 (ZO-1) and occludin, in the absence or presence of a heat stress-related damage of monolayer. Methods: TEER was evaluated on CaCo-2 differentiated monolayers. Epithelial permeability of polarized monolayers was assessed by measuring the FITC-labeled dextran flux from the apical to basolateral chambers. ZO-1/occludin levels were analyzed by western blot analysis. A set of experiments was performed to compare the effects of both VSL#3 on TEER values, dextran flux and ZO-1/occludin expression in CaCo-2 monolayers after heat stress exposure. Results: US- and Italy-made VSL#3 have opposing effects on TEER values, dextran flux, and ZO- 1/occludin expression, being all these parameters negatively influenced just by Italy-made product. US-made probiotic did not affect baseline TEER, dextran flux and ZO-1 expression and strongly increased occludin levels. Of note, pre-treatment of monolayer with US-made VSL#3, but not Italy-made product, totally prevented the heat-induced epithelial barrier integrity loss. Conclusion: Our data trigger the need for reassessing efficacy or safety of the Italy-made VSL#3 considering intestinal epithelial barrier plays an important role in maintaining host health.

Lethal in vitro effects of optimized chitosan nanoparticles against protoscoleces of Echinococcus granulosus

2021 ◽  
pp. 088391152110142
Author(s):  
Nima Firouzeh ◽  
Touba Eslaminejad ◽  
Reza Shafiei ◽  
Ashkan Faridi ◽  
Majid Fasihi Harandi
Keyword(s):  
Echinococcus Granulosus ◽  
Exposure Time ◽  
Chitosan Nanoparticles ◽  
Parasitic Infection ◽  
In Vivo Studies ◽  
Wide Range ◽  
In Vitro Effects ◽  
Scolicidal Agent

Cystic Echinococcosis (CE) is a parasitic infection caused by the larval stage of Echinococcus granulosus. Exploring safe and effective scolicidal agents for the surgery is an urgent need for the successful treatment of CE. This study aimed to determine scolicidal activity of the synthesized chitosan nanoparticles. Physicochemical properties of synthesized nanoparticles were determined by using DLS, FTIR, and SEM. Different concentrations of chitosan nanoparticles from 125 to 1000 μg/ml were examined at different incubation times (10, 60, 120, and 180 min). Scolicidal and cytotoxic activity of chitosan nanoparticles were confirmed by eosin exclusion and hemolysis activity tests. FTIR spectra, zeta potential (+42 ± 2.08) and PDI (0.388 ± 0.034) value revealed that the chitosan nanoparticles were synthesized. Significant differences among the scolicidal effects of chitosan nanoparticles were observed in comparison to the control treatments and highest scolicidal activity was observed at 1000 μg/ml after 180 min exposure time. Hemolytic activity was not significant at all concentrations of chitosan nanoparticles. Our findings support the hypothesis that Chitosan nanoparticles have the potential to be a safe and efficient scolicidal agent candidate at very low concentrations and in a wide range of exposure time. Further in vivo studies are recommended to evaluate chitosan nanoparticle efficacy before clinical application.

scholarly journals PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5′-Diphospho-glucuronosyltransferase Substrates

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1325
Author(s):  
Micaela B. Reddy ◽  
Michael B. Bolger ◽  
Grace Fraczkiewicz ◽  
Laurence Del Frari ◽  
Laibin Luo ◽  
...  
Keyword(s):  
Pbpk Modeling ◽  
Intestinal Metabolism ◽  
Human Gastrointestinal Tract ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
First Pass ◽  
In Vivo Extrapolation

Uridine 5′-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug–drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro–in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.

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