Speaker
Description
Our group at the University of Washington focuses on the development of microphysiological models as an alternative to animal testing. I will present case studies on the application of these new approach methodologies (NAMs) in modeling ADME disposition and toxicity of drugs, endobiotics and xenobiotics. These studies are based on the “holy trinity” of ADME NAMs-the intestine, liver and kidneys. In the first case study I will discuss how we used a linked liver-kidney NAM to demonstrate that NQO1 mediates the nephrotoxic effects of aristolochic acid (AA). AA is linked to Chinese herbal and Balkan endemic nephropathy, and we found that liver bioactivation mediates AA acute injury to the proximal tubule. The second case study will focus on an intestinal NAM to model extraction ratio of the benzodiazepine midazolam. Crypt stem cell-derived intestinal Transwell™ monolayers recapitulate both barrier function and CYP450 activities, demonstrating similar extraction ratios for midazolam to intact human intestine. Finally, I will present results of our studies from “Tissue Chips in Space” where we sent our kidney NAM to the International Space Station. In microgravity, there is a profound loss of bone density over time and astronauts are known to have lower levels of the active form of vitamin D (1,25(OH)2D). The kidney proximal tubule generates this metabolite via CYP27B1 hydroxylation of 25(OH)D; we tested whether this activity was compromised in kidney NAMs in microgravity. While metabolite levels were similar to 1g controls, we observed fourfold fewer differentially expressed genes in microgravity, suggesting 1,25(OH)2D-mediated signaling is blunted.
