Title:
Development of Human-Derived Cells to Recapitulate Organ Functions for ADME and Toxicity Studies.
Speaker:
Hiroyuki Kusuhara, Ph.D.
Professor, Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
In drug development, accurately predicting the efficacy and safety of candidate compounds in humans is a critical challenge. Since in vivo evaluation of efficacy and safety largely relies on experimental animals, it is essential to consider interspecies differences when transitioning from the nonclinical to clinical stages. Therefore, in vitro systems using human-derived cells are increasingly promoted as tools to overcome such species differences.
The small intestine is the primary site of absorption for orally administered drugs, facilitating the transfer of compounds from the lumen into the bloodstream. Absorptive epithelial cells express drug-metabolizing enzymes and transporters, which can limit drug absorption. Accordingly, the development of model systems that allow quantitative evaluation of the impact of these enzymes and transporters has been essential for predicting drug disposition. Recently, the establishment of culture methods for intestinal stem cells located in the crypts of the small intestine has enabled the development of advanced in vitro small intestinal models. We obtained crypts from surgical specimens and investigated the optimal differentiation conditions required to generate absorptive epithelial cells that recapitulate ADME functions.
For oral drugs, gastrointestinal (GI) toxicities such as diarrhea and vomiting are frequently observed adverse events in clinical trials. Taking advantage of the stem cells’ ability to differentiate into various cell types lining the intestinal epithelium, this model enables comprehensive assessment of the toxicity profiles of new chemical entities. We evaluated two distinct mechanisms of GI toxicity: proliferation inhibition mediated by EGFR tyrosine kinase inhibition, which is associated with diarrhea risk, and serotonin release from enterochromaffin cell-enriched organoids, which serves as a trigger for emesis and nausea. In addition to evaluating concentration-dependent cellular responses, we demonstrated a quantitative relationship between adverse clinical outcomes and in vitro metrics of the tested compounds.
This model represents a promising platform for translational safety assessment of gastrointestinal toxicity arising from diverse mechanisms, while also enabling the evaluation of pharmacokinetic properties such as intestinal metabolism and transporter-mediated absorption. It offers mechanistic insights and supports the selection of compounds with reduced GI toxicity and optimized absorption profiles in early-stage drug development.
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