Comparison of Human Long-Term Liver Models for Clearance Prediction of Slowly Metabolized Compounds.

The accurate prediction of human clearance is an important task during drug development. The proportion of low clearance compounds has increased in drug development pipelines across the industry since such compounds may be dosed in lower amounts and at lower frequency. These type of compounds present new challenges to in vitro systems used for clearance extrapolation.

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments.

Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates.

3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation.

Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and biomedicine. Notably, it has become clear that liver function can only be sustained in 3D culture systems at physiologically relevant cell densities. Additionally, drug metabolism and drug-induced cellular toxicity often follow distinct spatial micropatterns of the metabolic zones in the liver acinus, calling for models that capture this zonation.

Bioengineered Pancreas-Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia.

Aberrant glucose homeostasis is the most common metabolic disturbance affecting one in ten adults worldwide. Prediabetic hyperglycemia due to dysfunctional interactions between different human tissues, including pancreas and liver, constitutes the largest risk factor for the development of type 2 diabetes. However, this early stage of metabolic disease has received relatively little attention.

Multi-Well Array Culture of Primary Human Hepatocyte Spheroids for Clearance Extrapolation of Slowly Metabolized Compounds.

Accurate prediction of human pharmacokinetics using in vitro tools is an important task during drug development. Albeit, currently used in vitro systems for clearance extrapolation such as microsomes and primary human hepatocytes in suspension culture show reproducible turnover, the utility of these systems is limited by a rapid decline of activity of drug metabolizing enzymes. In this study, a multi-well array culture of primary human hepatocyte spheroids was compared to suspension and single spheroid cultures from the same donor.

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development-Current State-of-the-Art and Future Perspectives.

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time.

Deconvolution of Cytochrome P450 Induction Mechanisms in HepaRG Nuclear Hormone Receptor Knockout Cells.

Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and PXR/CAR knockout (KO) HepaRG cells, as well as a PXR reporter gene assay, were used to investigate the mechanism of CYP3A4 and CYP2B6 induction by prototypical substrates and a group of compounds from the Merck KGaA oncology drug discovery pipeline. The basal and inducible gene expression of CYP3A4 and CYP2B6 of nuclear hormone receptor (NHR) KO HepaRG relative to control HepaRG was characterized. The basal expression of CYP3A4 was markedly higher in the PXR (10-fold) and CAR (11-fold) KO cell lines compared with control HepaRG, whereas inducibility was substantially lower.

Bacterial microbiota diversity and composition in red and white wines correlate with plant-derived DNA contributions and botrytis infection.

Wine is a globally produced, marketed and consumed alcoholic beverage, which is valued for its aromatic and qualitative complexity and variation. These properties are partially attributable to the bacterial involvement in the fermentation process. However, the organizational principles and dynamic changes of the bacterial wine microbiota remain poorly understood, especially in the context of red and white wine variations and environmental stress factors.