Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites.

There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health. There are examples of PBK models that have implemented gut microbial biotransformation of xenobiotics with the gut as a dedicated metabolic compartment. However, the integration of microbial metabolism and parameterization of PBK models is not standardized and has only been applied to a few chemical transformations. A challenge in this area is the measurement of microbial metabolic kinetics, for which different fermentation approaches are used. Without a standardized method to measure gut microbial metabolism ex vivo/in vitro, the kinetic constants obtained will lead to conflicting conclusions drawn from model predictions. Nevertheless, there are specific cases where PBK models accurately predict systemic concentrations of gut microbial metabolites, offering potential solutions to the challenges outlined above. This review focuses on models that integrate gut microbial bioconversions and use ex vivo/in vitro methods to quantify metabolic constants that accurately represent in vivo conditions.

Physiologically-Based Pharmacokinetic Modeling of the Postbiotic Supplement Urolithin A Predicts its Bioavailability Is Orders of Magnitude Lower than Concentrations that Induce Toxicity, but also Neuroprotective Effects.

SCOPE: A range of health benefits are attributed to consuming urolithin A (UA), such as improved muscle health, anti-aging activity, and neuroprotection, whereas few studies raise possible adverse effects at high doses, including genotoxicity and estrogenic effects. Therefore, understanding UA bioactivity and safety depends on its pharmacokinetics. However, there is no physiologically-based pharmacokinetic (PBPK) model available for UA, thus limiting reliable assessment of effects observed from in vitro experimentation. METHODS AND RESULTS: We characterizes glucuronidation rates of UA by human S9 fractions. Partitioning and other physicochemical parameters are predicted using quantitative structure-activity relationship tools. Solubility and dissolution kinetics are determined experimentally. These parameters are used to construct a PBPK model, and results are compared with data from human intervention studies. We evaluates how different supplementation scenarios may influence UA plasma and tissue concentrations. Concentrations at which either toxic or beneficial effects are previously observed in vitro appear unlikely to be achieved in vivo. CONCLUSION: A first PBPK model for UA is established. It enables prediction of systemic UA concentrations and is critical for extrapolating in vitro results to in vivo uses. Results support the safety of UA, but also challenge the potential for readily achieving beneficial effects by postbiotic supplementation.

Breaking through the barrier: Modelling and exploiting the physical microenvironment to enhance drug transport and efficacy.

Pharmaceutical compounds are the main pillar in the treatment of various illnesses. To administer these drugs in the therapeutic setting, multiple routes of administration have been defined, including ingestion, inhalation, and injection. After administration, drugs need to find their way to the intended target for high effectiveness, and this penetration is greatly dependent on obstacles the drugs encounter along their path. Key hurdles include the physical barriers that are present within the body and knowledge of those is indispensable for progress in the development of drugs with increased therapeutic efficacy. In this review, we examine several important physical barriers, such as the blood-brain barrier, the gut-mucosal barrier, and the extracellular matrix barrier, and evaluate their influence on drug transport and efficacy. We explore various in vitro model systems that aid in understanding how parameters within the barrier model affect drug transfer and therapeutic effect. We conclude that physical barriers in the body restrict the quantity of drugs that can pass through, mainly as a consequence of the barrier architecture. In addition, the specific physical properties of the tissue can trigger intracellular changes, altering cell behavior in response to drugs. Though the barriers negatively influence drug distribution, physical stimulation of the surrounding environment may also be exploited as a mechanism to control drug release. This drug delivery approach is explored in this review as a potential alternative to the conventional ways of delivering therapeutics.