Bio: Dr. Georg Aichinger is Group Leader at the Laboratory of Toxicology of ETH Zürich, Switzerland. With a background in in vitro toxicology and mixture effects, his group now focuses on toxicokinetics and gut microbiome-chemical interactions. His main goal is to develop and refine microbiome-competent physiologically based kinetic models to facilitate quantitative in vitro to in vivo extrapolation for assessing the hazard of gut microbial biotransformation products.

Abstract: Xenobiotic metabolism in the liver is classically considered the defining process of toxicokinetics, but gut microbiota recently emerged as significant contributors to chemical biotransformation. Consequently, there is a need to develop methods that predict microbiome-mediated bioactivation and detoxification processes. We thus established microbiome-competent PBK models for two distinct chemicals of interest and demonstrated their applicability for quantitative in vitro to in vivo extrapolation. First, we tested and evaluated modeling strategies focusing on urolithin A, a gut microbial metabolite with extensive human pharmacokinetic data availability. The model incorporates urolithin formation in the gut, gastrointestinal absorption, partitioning to organs of interest, glucuronidation in the liver and small intestine, urinary excretion, as well as enterohepatic circulation. UA formation rates were derived from anaerobic batch fermentations using stool samples from 22 volunteers. After evaluation, we utilized the model to understand how concentrations for biological effects, previously reported in vitro, relate to predicted concentrations in target tissues. Second, we used the same conceptual model to evaluate the systemic impact of interindividual differences in the gut microbial formation of the endocrine disruptor 8-prenylnaringenin from hop polyphenols. Predicted internal exposures in organs of interest were subsequently used to extrapolate in vitro concentration-response data to in vivo effects.