Article
Pharmacology & Pharmacy
Marlies Oorts, Pieter Van Brantegem, Neel Deferm, Sagnik Chatterjee, Erwin Dreesen, Axelle Cooreman, Mathieu Vinken, Lysiane Richert, Pieter Annaert
Summary: Bosentan was evaluated at therapeutically relevant concentrations (2.5-25 μM) in sandwich-cultured human hepatocytes. It altered bile salt disposition and inhibited canalicular secretion of glycochenodeoxycholic acid (GCDCA). Within 24 hours, bosentan caused a shift from canalicular to sinusoidal efflux of GCDCA. These results also indicated reduced GCDCA formation. This study confirmed a direct effect of bosentan on chenodeoxycholic acid conjugation with glycine in liver S9 fraction.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Pharmacology & Pharmacy
Congrong Niu, Bill Smith, Yurong Lai
Summary: This study characterized the gene induction by ligands of CAR and AhR in human hepatocytes, showing distinct effects on metabolizing enzyme and drug transporter genes. Different inducers had varying degrees of effects on specific genes, highlighting the importance of assessing transporter gene inductions alongside metabolizing enzyme genes.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Taleah Farasyn, Sonia Pahwa, Chao Xu, Wei Yue
Summary: This study demonstrates that pre-incubation with OATP1B inhibitors potentiates inhibitory effects in physiologically relevant primary human hepatocytes, supporting the rationale of the current US FDA draft guidance. IC50 values after inhibitor-preincubation in transporter-expressing cell lines may be used for DDI prediction for the purpose of mitigating false-negative OATP-mediated DDI prediction.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Chemistry, Medicinal
Takashi Yoshikado, Wooin Lee, Kota Toshimoto, Kiyoe Morita, Aya Kiriake, Xiaoyan Chu, Nora Lee, Emi Kimoto, Manthena V. S. Varma, Ryota Kikuchi, Renato J. Scialis, Hong Shen, Naoki Ishiguro, Ralf Lotz, Albert P. Li, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama
Summary: Hepatic uptake clearances of OATP1B substrates were compared between plated human hepatocytes (PHH) and suspended human hepatocytes (SHH), showing differences in uptake kinetics and cell-to-medium concentration ratios. PHH is useful for high-throughput evaluation of hepatic uptake/efflux clearances and Kp,Kuu, with caution needed for hydrophilic drugs with low uptake/cellular binding.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Li Wang, Zhiyao Zhu, Doanh Tran, Shirley K. Seo, Xiaolei Pan
Summary: The study estimated hepatobiliary clearances of rosuvastatin by simultaneously fitting to human positron emission tomography data in the liver and gallbladder. The established hepatobiliary model captured the kinetic profiles of rosuvastatin well, highlighting the importance of using hepatobiliary data for predicting hepatic disposition of rosuvastatin.
PHARMACEUTICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Angela Jeong, Catherine M. Pastor, Kim L. R. Brouwer
Summary: In this study, a multi-compartmental pharmacokinetic (PK) model was developed to describe the hepatic disposition of two imaging agents in normal and liver-damaged rats. The results showed differential uptake and efflux rates between the two agents in hepatocytes and extracellular space. This PK model could be used to assess changes in hepatic uptake and efflux of these imaging agents in response to disease, toxicity, or drug-drug interactions.
PHARMACEUTICAL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Irene Hernandez-Lozano, Severin Mairinger, Michael Sauberer, Johann Stanek, Thomas Filip, Thomas Wanek, Giuliano Ciarimboli, Nicolas Tournier, Oliver Langer
Summary: The study investigated the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of [C-11]metoclopramide in mice. Results showed that OCT1/2 contribute to kidney and liver uptake, while MATEs play a role in urinary excretion of the drug. Cation transporters may contribute to variability in metoclopramide pharmacokinetics and side effects.
PHARMACEUTICAL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Tomoki Imaoka, Weize Huang, Sara Shum, Dale W. Hailey, Shih-Yu Chang, Alenka Chapron, Catherine K. Yeung, Jonathan Himmelfarb, Nina Isoherranen, Edward J. Kelly
Summary: A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.
SCIENTIFIC REPORTS
(2021)
Article
Pharmacology & Pharmacy
Ningjie Xie, Hong Wang, Hua Qin, Zitao Guo, Hao Xue, Jiafeng Hu, Xiaoyan Chen
Summary: This study demonstrates that hepatic impairment can affect the metabolism and transport of ezetimibe and its metabolites, and the increased plasma exposure of ezetimibe during hepatic dysfunction is attributed to decreased glucuronide conjugation, while the increased exposure of the metabolite is mainly related to transporter activity, particularly the inhibitory effects of bile acids on organic anion transporting polypeptides (OATPs) after oral administration.
Article
Pharmacology & Pharmacy
Melanie Golding, Oliver Light, Beth Williamson, Karelle Menochet
Summary: This study identified selective substrates and inhibitors for the main human hepatocyte transporters and demonstrated their use in rapidly characterizing hepatocyte activity. The findings provide important information for compound interactions with uptake transporters, aiding in early risk assessment and chemistry design.
Article
Chemistry, Multidisciplinary
Ya-li Wu, Ya-ru Xue, Zi-tao Guo, Zhen-dong Chen, Xin-yu Ge, Da-fang Zhong, Xing-xing Diao
Summary: Furmonertinib has been identified as a potent CYP3A4 inducer, comparable to rifampin, making it a potential positive control for evaluating the induction potential of other drug candidates in preclinical studies. Results from the study show that furmonertinib induced CYP3A4 enzyme activity in a manner similar to rifampin in in vitro experiments.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Neurosciences
Marta S. Sousa, Joao L. Alves, Johnattan C. S. Freitas, Joao N. Miraldo, Fernando D. S. Sampaio dos Aidos, Rosa M. Santos, Luis M. Rosario, Rosa M. Quinta-Ferreira, M. Emilia Quinta-Ferreira, Carlos M. Matias
Summary: Zinc is abundant in the mossy fibers of the hippocampal CA3 area and its role in synaptic mechanisms is still not fully understood. Computational models have been used to study the dynamics of zinc at the mossy fiber synaptic cleft. The models were extended to include postsynaptic zinc effluxes and the results showed that the main escape routes for cleft zinc are L-type calcium channels, NMDA receptor channels, and N-type calcium channels.
Article
Pharmacology & Pharmacy
Taleah Farasyn, Chao Xu, Wei Yue
Summary: The study aimed to develop a novel rat SCH model expressing human OATP1B3 to study the hepatic disposition of OATP1B3 substrates. The results showed that expressing human OATP1B3 in rat SCH significantly increased the cellular accumulation of OATP1B3 substrates without affecting biliary excretion.
JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
(2021)
Article
Toxicology
Takashi Kitaguchi, Shinichiro Horiuchi, Yukie Kuroda, Katsutoshi Ohno, Kazuhiro Kobayashi, Mitsuru Tanaka, Seiichi Ishidaz
Summary: A simple in vitro culture method using cryopreserved human hepatocytes was developed to generate extended and functional bile canaliculi, and to evaluate the uptake and biliary excretion of compounds. Positive biliary excretion index (BEI) was observed for reported biliary-excreted compounds, while no difference in BEI was seen for a nonbiliary-excreted compound. Additionally, specific food-related compounds with reported biliary transporter involvement exhibited positive BEIs. This in vitro system can be used to predict the biliary excretion of pharmaceutical and food-related compounds.
JOURNAL OF TOXICOLOGICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Qian Yang, Albert P. Li
Summary: The study showed that while human hepatocytes underwent dedifferentiation after 2 days of culture, prolonged culturing resulted in redifferentiation based on gene expression. The observed redifferentiation suggests that prolonged (>7 days) culturing of human hepatocyte cultures may represent an experimental approach to overcome the initial dedifferentiation process.
DRUG METABOLISM AND DISPOSITION
(2021)
Article
Toxicology
E. E. J. Kasteel, K. Darney, N. Kramer, J. L. C. M. Dorne, L. S. Lautz
ARCHIVES OF TOXICOLOGY
(2020)
Article
Toxicology
Diane M. Longo, Lisl K. M. Shoda, Brett A. Howell, Vladimir Coric, Robert M. Berman, Irfan A. Qureshi
TOXICOLOGICAL SCIENCES
(2020)
Article
Toxicology
Brenda Smith, Josh Rowe, Paul B. Watkins, Messoud Ashina, Jeffrey L. Woodhead, Frank D. Sistare, Peter J. Goadsby
TOXICOLOGICAL SCIENCES
(2020)
Article
Medicine, Legal
Gary Eichenbaum, Kyunghee Yang, Yeshitila Gebremichael, Brett A. Howell, F. Jay Murray, David Jacobson-Kram, Hartmut Jaeschke, Edwin Kuffner, Cathy K. Gelotte, John C. K. Lai, Daniele Wikoff, Evren Atillasoy
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2020)
Review
Medicine, Legal
F. Jay Murray, Andrew D. Monnot, David Jacobson-Kram, Samuel M. Cohen, Jerry F. Hardisty, Suren B. Bandara, Michael Kovochich, Milind Deore, Suresh Kumar Pitchaiyan, Cathy K. Gelotte, John C. K. Lai, Evren Atillasoy, Anne Hermanowski-Vosatka, Edwin Kuffner, Kenneth M. Unice, Kyunghee Yang, Yeshitila Gebremichael, Brett A. Howell, Gary Eichenbaum
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Cosimo Toma, Alberto Manganaro, Giuseppa Raitano, Marco Marzo, Domenico Gadaleta, Diego Baderna, Alessandra Roncaglioni, Nynke Kramer, Emilio Benfenati
Summary: This study developed classification and regression models for inhalation and oral slope factors, which showed good accuracy and R^2 values. These models may assist regulatory authorities in decision-making and weighing evidence in chemical safety assessments.
Review
Toxicology
Susana Proenca, Beate Escher, Fabian C. Fischer, Ciaran Fisher, Sebastien Gregoire, Nicky J. Hewitt, Beate Nicol, Alicia Paini, Nynke Kramer
Summary: Nominal effect concentrations from in vitro toxicity assays can lead to inaccurate estimations of in vivo toxic doses. Chemicals distribute differently between in vitro assay compartments, affecting representative concentrations, while free concentrations and cell-associated concentrations can better represent the biologically effective dose.
TOXICOLOGY IN VITRO
(2021)
Review
Pharmacology & Pharmacy
Matteo R. Di Nicola, Andrea Pontara, George E. N. Kass, Nynke Kramer, Ignazio Avella, Riccardo Pampena, Santo Raffaele Mercuri, Jean Lou C. M. Dorne, Giovanni Paolino
Summary: Snakebites in Europe are mainly caused by species of the Vipera genus in the Viperidae family. The venom composition is diverse, leading to various symptoms ranging from pain to tissue damage. Prompt immobilization, compression, and appropriate medical treatment are crucial for managing snakebites effectively.
Review
Pharmacology & Pharmacy
Mathieu Vinken, Emilio Benfenati, Francois Busquet, Jose Castell, Djork-Arne Clevert, Theo M. de Kok, Hubert Dirven, Ellen Fritsche, Liesbet Geris, Rafael Gozalbes, Thomas Hartung, Danyel Jennen, Ramiro Jover, Helena Kandarova, Nynke Kramer, Cyrille Krul, Thomas Luechtefeld, Rosalinde Masereeuw, Erwin Roggen, Stephan Schaller, Tamara Vanhaecke, Chihae Yang, Aldert H. Piersma
Summary: The 3Rs concept, focusing on replacement, reduction, and refinement of animal experimentation, is gaining attention worldwide and has been incorporated into legislation, particularly in the European Union. The ONTOX project in Europe aims to develop AI-driven methods for repeated dose toxicity testing of chemicals without the use of animals to advance human risk assessment. This project will have a significant impact on consolidating Europe's leading position in the development and application of animal-free methods for chemical risk assessment.
Article
Toxicology
Emma E. J. Kasteel, Leonie S. Lautz, Maxime Culot, Nynke Kramer, Anne Zwartsen
Summary: Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues without the need for animal experiments, but in vivo data are often used to parameterise them. This study demonstrates that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models for neurologically-active chemicals. Using in vitro data, the study successfully predicted concentrations in the central nervous system for different administration routes, showing the accuracy of PBK models without additional in vivo data.
TOXICOLOGY IN VITRO
(2021)
Article
Environmental Sciences
Sreya Ghosh, Jonathan De Smedt, Tine Tricot, Susana Proenca, Manoj Kumar, Fatemeharefeh Nami, Thomas Vanwelden, Niels Vidal, Paul Jennings, Nynke I. Kramer, Catherine M. Verfaillie
Summary: Traditional toxicity risk assessment methods have focused on histochemical readouts for cell death, while modern toxicology methods attempt to understand toxicity pathways using transcriptomics and big data-driven approaches. By differentiating human induced pluripotent stem cells into hepatocyte-like cells, researchers were able to accurately classify chemicals causing acute hepatocellular injury and identify stress pathways linked to cytotoxicity. This method may be more sensitive in detecting differentially expressed genes compared to existing datasets, making it suitable for chemical toxicity detection and mechanistic toxicity studies.
Article
Toxicology
Abdulkarim Najjar, Ans Punt, John Wambaugh, Alicia Paini, Corie Ellison, Styliani Fragki, Enrica Bianchi, Fagen Zhang, Joost Westerhout, Dennis Mueller, Hequn Li, Quan Shi, Timothy W. Gant, Phil Botham, Remi Bars, Aldert Piersma, Ben van Ravenzwaay, Nynke I. Kramer
Summary: With the increasing need for new methodologies and the phasing out of animal testing, interpreting in vitro assay results for quantitative hazard characterization is becoming more important. Physiologically based kinetic (PBK) models play a crucial role in extrapolating in vitro concentrations to in vivo exposures. Standardizing PBK modeling approaches is necessary for regulatory risk assessment and several steps are recommended for improvement, including defining context and implementation, harmonizing physiological input parameters, applying Good Modeling Practices (GMP), and evaluating model predictions using alternatives to in vivo data.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Medicine, Legal
Styliani Fragki, Aldert H. Piersma, Joost Westerhout, Anne Kienhuis, Nynke I. Kramer, Marco J. Zeilmaker
Summary: This article discusses the shift from animal testing to in vitro tools in toxicology research and introduces a quantitative method - kinetic modelling - for assessing chemical safety. The study shows that computational models and in vitro parameters can accurately simulate toxicokinetics.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Manon C. Bouwmeester, Yu Tao, Susana Proenca, Frank G. van Steenbeek, Roos-Anne Samsom, Sandra M. Nijmeijer, Theo Sinnige, Luc J. W. van der Laan, Juliette Legler, Kerstin Schneeberger, Nynke I. Kramer, Bart Spee
Summary: In vitro toxicity testing using hepatocyte-like intrahepatic cholangiocyte organoids (HL-ICOs) allows for the evaluation of drug metabolism gene expression and activity, providing insights into the extent of drug-induced hepatotoxicity.
Article
Pharmacology & Pharmacy
Susana Proenca, Nick van Sabben, Juliette Legler, Jorke H. Kamstra, Nynke I. Kramer
Summary: This study investigates the effects of hexabromocyclododecane (HBCD) on human liver cells using different cell models. The 3D model exhibited the strongest response to HBCD, but none of the models showed changes in enzyme activity related to thyroid hormone metabolism. This suggests that transcriptome changes may not accurately reflect the adverse effects of HBCD on thyroid hormone.