StemCell Therapy

Inadequate prediction of drug metabolism or toxicity is the Achilles heel of the pharmaceutical industry, leading to high drug attrition rates. This can have significant implications for companies, with late-stage failure typically resulting in the loss of substantial financial investments, time and resources. By defining and predicting the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profile of compounds as early as possible, companies can focus their resources on the most relevant candidates to increase the likelihood of successfully bringing new safe and efficient therapies to the market.To implement early ADME-Tox testing, its crucial to have access to valid in vitro models of the key sites of drug metabolism the liver, kidneys and intestines. Preclinical models that reliably replicate the in vivo cellular environment of these organs enable scientists to study and accurately predict drug metabolism, transport and toxicity prior to targets entering the clinical trial phase, ultimately helping to lower attrition rates.

For many years, biologists have relied on in vitro 2-dimensional (2D) cell culture models to perform preclinical ADME-Tox assays. While these models are useful for informing aspects of drug discovery, such as cytotoxicity, they are limited in their translatability to drug metabolism and toxicity in humans. Recently, in vitro 3-dimensional (3D) organoid models that more closely mimic human biological systems show promise in supporting ADME-Tox studies in the early stages of the drug development process, compared to their 2D counterparts.

For modeling kidney cell function in vitro and to evaluate general nephrotoxicity, researchers use various types of human proximal tubule cell lines. These cells demonstrate specific properties of the kidney epithelium, such as the transport of solutes, which plays an important role in drug excretion,. Limitations of these in vitro models are due to the different cell types not expressing all necessary transporters, metabolizing enzymes or biomarkers at physiological levels.3

Given these challenges, there is a clear need for advanced in vitro 3D models that more accurately emulate drug permeability, metabolism, transport and toxicity in humans.

Due to a greater understanding of the cell microenvironment, organoid technology has advanced over the last few years and has the potential to streamline the drug development process. Using organoids to support in vitro ADME-Tox studies can help to predict metabolic mechanisms and ascertain key safety and efficacy measures before commencing human clinical trials. Evidence suggests that kidney and intestine organoid models could be more valuable to investigate the metabolism, transport and toxicity of drugs.3,4 Indeed, a kidney organoid model has recently been cultured using human induced pluripotent stem cells. Composed of both glomerular tissue, as well as proximal and distal tubule cells, this model offers a more accurate representation of the kidney. As such, it has the potential to inform and refine preclinical toxicity screening studies.3

In another recent study, human primary cells from intestinal epithelium was engineered into a 3D intestinal organoid using a scaffold system [4]. This model showed complex tissue properties and characteristics of mature epithelium, including the four main types of differentiated epithelial cells (enterocytes, goblet cells, paneth cells and enteroendocrine cells). The tight junction formation, microvilli polarization, digestive enzyme secretion and low oxygen tension in the lumen were also representative of mature epithelium. In addition to these physical properties, the organoids also exhibited complex behavior, such as innate antibacterial responses to E. coli similar to those observed in patients with inflammatory bowel disease (IBD). This suggests that the model could be used in in vitro studies investigating host-microbe-pathogen interplay and IBD pathogenesis.

These findings highlight the future potential of in vitro 3D kidney and intestine organoids for drug development. Because these systems closer resemble in vivo tissues, they could help predict drug responses early in development and offer vast possibilities for modeling many diseases in the future.

1. Van Breemen R.B and Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):17585

2. Yamaura Y, et al. Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism. Drug Metabolism and Disposition. March 2016;44:329335

3. Bajaj P, et al. Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics. Drug Metabolism and Disposition. November 2018;46(11):16921702

4. Chen Y, et al. In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS One. 2017;12(11): e0187880

Read more:
The Promise of in vitro 3D Organoid Models: Meeting the ADME-Tox Testing Needs of the Pharmaceutical Industry - Technology Networks

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