Toward Realistic Dosimetry <i>In Vitro</i>: Determining Effective Concentrations of Test Substances in Cell Culture and Their Prediction by an <i>In Silico</i> Mass Balance Model

Dimitrijevic, Dunja; Fabian, Eric; Nicol, Beate; Funk-Weyer, Dorothee; Landsiedel, Robert

doi:10.1021/acs.chemrestox.2c00128

Cited by 11 publications

(4 citation statements)

References 69 publications

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“…To improve the comparison between different cell systems, it is essential to determine the concentration that is actually available to be taken up by the cells in the in vitro system. In the case of lipophilic compounds such as perhexiline, in vitro system components such as Matrigel or medium components can decrease this available concentration [ 56 , 57 ]. In the case of bupropion (CYP2B6 activity), abiotic degradation of the compound was observed, especially in the HL-ICOs.…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

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Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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“…In vitro methods for determining air to blood partition coefficients include artificial membrane models, liquid–liquid extraction, Parallel Artificial Membrane Permeability Assay (PAMPA), cell culture models, , and Selected Ion Flow Tube Mass Spectrometry (SIFT-MS). , Additionally, chromatographic techniques, like gas chromatography (GC) and liquid chromatography (LC), can also be used, with two-dimensional gas chromatography (GC×GC) being a powerful tool, offering enhanced resolution for volatile compound analysis and their complex mixtures. , Despite avoiding live animal testing and reducing ethical concerns, in vitro testing has drawbacks like being costly, laborious, and complex. , …”

Section: Introductionmentioning

confidence: 99%

Novel Models for Accurate Estimation of Air–Blood Partitioning: Applications to Individual Compounds and Complex Mixtures of Neutral Organic Compounds

Aakash,

Kulsoom,

Khan

et al. 2023

J. Chem. Inf. Model.

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The air-blood partition coefficient (K ab ) is extensively employed in human health risk assessment for chemical exposure. However, current K ab estimation approaches either require an extensive number of parameters or lack precision. In this study, we present two novel and parsimonious models to accurately estimate K ab values for individual neutral organic compounds, as well as their complex mixtures. The first model, termed the GC×GC model, was developed based on the retention times of nonpolar chemical analytes on comprehensive two-dimensional gas chromatography (GC×GC). This model is unique in its ability to estimate the K ab values for complex mixtures of nonpolar organic chemicals. The GC×GC model successfully accounted for the K ab variance (R 2 = 0.97) and demonstrated strong prediction power (RMSE = 0.31 log unit) for an independent set of nonpolar chemical analytes. Overall, the GC×GC model can be used to estimate K ab values for complex mixtures of neutral organic compounds. The second model, termed the partition model (PM), is based on two types of partition coefficients: octanol to water (K ow ) and air to water (K aw ). The PM was able to effectively account for the variability in K ab data (n = 344), yielding an R 2 value of 0.93 and rootmean-square error (RMSE) of 0.34 log unit. The predictive power and explanatory performance of the PM were found to be comparable to those of the parameter-intensive Abraham solvation models (ASMs). Additionally, the PM can be integrated into the software EPI Suite, which is widely used in chemical risk assessment for initial screening. The PM provides quick and reliable estimation of K ab compared to ASMs, while the GC×GC model is uniquely suited for estimating K ab values for complex mixtures of neutral organic compounds. In summary, our study introduces two novel and parsimonious models for the accurate estimation of K ab values for both individual compounds and complex mixtures.

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“…It is obvious that the quantification of Colc content in pharmaceutical and biological samples is very important in order to monitor the treatment of patients and perform pharmacological studies. Several analytical methods have been reported for Colc quantification, such as high-performance liquid chromatography (HPLC), mass spectroscopy (MS), spectrophotometry, HPLC-MS, and HPLC-UV [ 11 , 12 , 13 , 14 , 15 ]. Despite the advantages of these techniques, they require time-consuming sample preparation procedures and expensive instrumentation.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Determination of the Drug Colchicine in Pharmaceutical and Βiological Samples Using a 3D-Printed Device

Filopoulou,

Michail,

Katseli

et al. 2023

Molecules

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In this work, a simple, fast, and sensitive voltammetric method for the trace determination of the alkaloid drug colchicine (Colc) using a 3D-printed device is described. The electrochemical method was based on the adsorptive accumulation of the drug at a carbon-black polylactic acid (CB/PLA) working electrode, followed by voltammetric determination of the accumulated species. The plastic sensor was printed in a single step by a low-cost dual extruder 3D-printer and featured three CB/PLA electrodes (serving as working, reference, and counter electrodes) and a holder, printed from a non-conductive PLA filament. The electrochemical parameters that affected the response of the device towards Colc determination, such as accumulation time and potential, solution pH, and other variables, were optimized. Under the selected conditions, the oxidation current of Colc was proportional to the concentration of Colc, and its quantification was conducted in the concentration range of 0.6–2.2 μmol L−1 with a limit of detection of 0.11 μmol L−1 in phosphate buffer (pH 7.0). Both within-device and between-device reproducibility were lower than 9%, revealing satisfactory operational and fabrication reproducibility. Furthermore, the 3D-printed device was employed for the voltammetric determination of Colc in pharmaceutical tablets and in human urine with satisfactory results, justifying its suitability for low-cost routine analysis of Colc.

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Toward Realistic Dosimetry In Vitro: Determining Effective Concentrations of Test Substances in Cell Culture and Their Prediction by an In Silico Mass Balance Model

Cited by 11 publications

References 69 publications

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Novel Models for Accurate Estimation of Air–Blood Partitioning: Applications to Individual Compounds and Complex Mixtures of Neutral Organic Compounds

Electrochemical Determination of the Drug Colchicine in Pharmaceutical and Βiological Samples Using a 3D-Printed Device

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