Current status and future directions of high-throughput ADME screening in drug discovery

Journal of Pharmaceutical Analysis, Journal Year: 2020, Volume and Issue: 10(3), P. 201 - 208

Published: May 23, 2020

During the last decade high-throughput in vitro absorption, distribution, metabolism and excretion (HT-ADME) screening has become an essential part of any drug discovery effort synthetic molecules. The conduct HT-ADME been "industrialized" due to extensive development software automation tools cell culture, assay incubation, sample analysis data analysis. portfolio continues expand emerging areas such as drug-transporter interactions, early soft spot identification, ADME peptide candidates. Additionally, thanks very large high-quality sets available many biopharma companies, silico prediction properties using machine learning also gained much momentum recent years. In this review, we discuss current state-of-the-art practices including portfolio, automation, analysis, processing, model building. addition, offer perspectives future exciting field.

Language: Английский

---

Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism, and accumulation

Clinical and Translational Science, Journal Year: 2020, Volume and Issue: 14(3), P. 1049 - 1061

Published: Dec. 31, 2020

Abstract Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs not routinely used in development due to lack of criteria ensuring reproducibility results. We characterized the feasibility liver MPS yield reproducible outcomes experiments assaying toxicity, metabolism, and intracellular accumulation. The ability reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made two test sites with different batches Kupffer cells. Upon culturing equivalent hepatocytes MPS, spheroids, sandwich cultures, differences between culture formats detected CYP3A4 activity albumin production. Cells all exhibited sensitivities hepatotoxicant exposure. Hepatocytes more functionally stable than those other platforms, as secretion remained prominent greater 18 days culture, whereas functional decline occurred earlier spheroids (12 days) cultures (7 days). also demonstrated be suitable metabolism studies, where activity, troglitazone metabolites, diclofenac clearance, accumulation chloroquine quantified. To ensure studies combined use LDH assays implemented quality control metrics. Overall results indicated that can reproducibly general evaluation applications. Study led considerations recommendations MPSs. Highlights WHAT IS THE CURRENT KNOWLEDGE ON TOPIC? Microphysiological have been designed recreate organ‐ or tissue‐specific characteristics extracellular microenvironments enhance physiological relevance cells culture. enable long‐lasting by them three‐dimensions exposing fluid flow. QUESTION DID THIS STUDY ADDRESS? What is performance relative cell platforms assessing questions, such pharmacokinetics? DOES ADD TO OUR KNOWLEDGE? systematically toxicity trovafloxacin. When compared this system had function sensitivity troglitazone, tamoxifen, digoxin. Quantifying phase II potential studying pharmacokinetics. Quality chip key reliably MPS. HOW MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Due its robustness (3D expose flow co‐culture types), can, manner: (i) detect inflammatory‐induced (ii) drugs, digoxin, (iii) rely on prolonged cellular (iv) metabolites potentially support interpretation clinical data. integration will facilitated careful performed study.

Language: Английский

---

Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system

APL Bioengineering, Journal Year: 2021, Volume and Issue: 5(3)

Published: July 30, 2021

The complexity of the human brain creates significant, almost insurmountable challenges for neurological drug development. Advanced

Language: Английский

---

Application of a gut–liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil

Lab on a Chip, Journal Year: 2022, Volume and Issue: 22(15), P. 2853 - 2868

Published: Jan. 1, 2022

Microphysiological systems (MPS) consisting of multiple linked organ-on-a-chip (OoC) components are highly promising tools with potential to provide more relevant in vitro vivo translation drug disposition, efficacy and toxicity. A gut-liver OoC system was employed Caco2 cells co-culture HT29 the intestinal compartment single donor primary hepatocytes hepatic for investigation permeability, metabolism (intestinal hepatic) interplay those processes. The prodrug mycophenolate mofetil tested quantitative evaluation due contribution both gut liver its metabolism. Conversion active mycophenolic acid further a glucuronide metabolite assessed over time apical, basolateral compartments. Mechanistic modelling experimental data performed estimate clearance permeability parameters prodrug, metabolite. Integration silico allowed complex combination processes, which is not possible standard tissue systems. comprehensive mechanistic model, including structural model parameter identifiability global sensitivity analysis, enabled robust design estimation pharmacokinetic parameters. We propose that similar methodologies may be applied other multi-organ microphysiological used studies or wherever knowledge changing concentration enables better understanding biological effect.

Language: Английский

---

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

Open Biology, Journal Year: 2022, Volume and Issue: 12(3)

Published: March 1, 2022

Non-clinical models to study metabolism including animal and cell assays are often limited in terms of species translatability predictability human biology. This field urgently requires a push towards more physiologically accurate recapitulations drug interactions disease progression the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), an emerging technology that is well suited providing species-specific platform various types (glucose, lipid, protein drug) by recreating organ-level function. review provides resource for scientists aiming overview MOCs recapitulating aspects metabolism, addressing technical MOC development guidelines correlation with silico models. The current state challenges presented two application areas: (i) modelling (ii) pharmacokinetics/pharmacodynamics. Additionally, integrate data into could strengthen predictive power technology. Finally, translational metabolizing addressed, adoption personalized medicine prospects clinic. Predictive enable significantly reduced dependence on open doors economical non-clinical testing understanding mechanisms.

Language: Английский

---

The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development

Pharmacological Research, Journal Year: 2023, Volume and Issue: 195, P. 106853 - 106853

Published: July 18, 2023

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared conventional and vivo models. In this review, the potential of OoC improve prediction human oral bioavailability intrinsic clearance is discussed, a focus on functionality application current drug development practice. Multi-OoC demonstrating for pharmacokinetic (PK) studies are summarized existing challenges identified. Physiological parameters minimal viable platform multi-OoC model study PK provided, together specific read-outs recommendations relevant reference compounds validate model. Finally, translation profiles which will be required routinely apply during development.

Language: Английский

---

Gut–liver microphysiological systems revealed potential crosstalk mechanism modulating drug metabolism

PNAS Nexus, Journal Year: 2024, Volume and Issue: 3(2)

Published: Feb. 1, 2024

Abstract The small intestine and liver play important role in determining oral drug's fate. Both organs are also interconnected through enterohepatic circulation, which imply there crosstalk circulating factors such as signaling molecules or metabolites that may affect drug metabolism. Coculture of hepatocytes intestinal cells have shown to increase hepatic metabolism, yet its mechanism is still unclear. In this study, we aim elucidate by coculturing primary human harvested from chimeric mouse (PXB-cells) iPSc-derived a microphysiological systems (MPS). Perfusion direct oxygenation the MPS were chosen confirmed be suitable features enhanced PXB-cells albumin secretion, cytochrome P450 (CYP) enzymes activity while maintaining barrier integrity cells. Results RNA-sequencing showed significant upregulation gene ontology terms related fatty acids metabolism PXB-cells. One acids, arachidonic acid, several CYP enzyme similar manner coculture. From current evidences, it speculated release bile acted stimuli for lipoprotein was ultimately taken activity.

Language: Английский

---

Basic models to advanced systems: harnessing the power of organoids-based microphysiological models of the human brain

Biofabrication, Journal Year: 2024, Volume and Issue: 16(3), P. 032007 - 032007

Published: May 15, 2024

Abstract Understanding the complexities of human brain’s function in health and disease is a formidable challenge neuroscience. While traditional models like animals offer valuable insights, they often fall short accurately mirroring biology drug responses. Moreover, recent legislation has underscored need for more predictive that represent physiology. To address this requirement, human-derived cell cultures have emerged as crucial alternative biomedical research. However, static culture lack dynamic tissue microenvironment governs function. Advanced vitro systems, such organoids microphysiological systems (MPSs), bridge gap by offering accurate representations biology. Organoids, which are three-dimensional miniaturized organ-like structures derived from stem cells, exhibit physiological responses akin to native tissues, but essential tissue-specific components functional vascular immune cells. Recent endeavors focused on incorporating endothelial cells into enhance vascularization, maturation, modeling. MPS, including organ-on-chip technologies, integrate diverse types vascularization under conditions, revolutionizing brain research bridging between vivo models. In review, we delve evolution with particular focus highlighting significance enhancing viability, functionality, modeling potential organoids. By examining interplay vasculature neuronal within organoids, can uncover novel therapeutic targets gain insights mechanisms, promise significant advancements neuroscience improved patient outcomes.

Language: Английский

---

Bridging the academia-to-industry gap: organ-on-a-chip platforms for safety and toxicology assessment

Trends in Pharmacological Sciences, Journal Year: 2021, Volume and Issue: 42(9), P. 715 - 728

Published: June 27, 2021

Language: Английский

---

Intestinal explant barrier chip: long-term intestinal absorption screening in a novel microphysiological system using tissue explants

Lab on a Chip, Journal Year: 2021, Volume and Issue: 22(2), P. 326 - 342

Published: Nov. 29, 2021

The majority of intestinal in vitro screening models use cell lines that do not reflect the complexity human tract and hence often fail to accurately predict drug absorption. Tissue explants have intact architecture type diversity, but show short viability static conditions. Here, we present a medium throughput microphysiological system, Intestinal Explant Barrier Chip (IEBC), creates dynamic microfluidic microenvironment prolongs tissue viability. Using snap fit mechanism, successfully incorporated porcine colon studied functionality, integrity for 24 hours. With proper distinction transcellular over paracellular transport (ratio >2), functionality was good at early late timepoints. Low leakage FITC-dextran preserved intracellular lactate dehydrogenase levels indicate maintained viability, respectively. From selection low high permeability drugs, 6 out 7 properly ranked according their fraction absorbed. In conclusion, IEBC is novel platform benefitting from flow chips.

Language: Английский

---