Pharmacokinetic Mechanisms Underlying Drug-Dietary Substance Interactions
Interpatient variability in drug response is an ongoing complication in clinical practice that can delay, or even prevent, optimal therapeutic outcomes, with consequent negative impact on quality of life and health care costs. While substantial resources have been invested in delineating genetic factors associated with variability in drug response, comparatively less attention has been given to non-genetic, environmental factors. Intentional ingestion of dietary substances, as foods or supplements, likely constitutes the largest portion of environmental exposure to chemicals.
Our lab is focused on the development of translational research methodologies aimed at prospective evaluation of drug-dietary substance interactions, which are especially challenging to assess because, unlike most drug products, dietary substances are mixtures, composed of multiple, and often unknown, bioactive ingredients. We are using silymarin, an extract of the top ten-selling supplement milk thistle, and grapefruit juice (GFJ) as model dietary substances to test the central hypothesis that an interactive in vitro-in silico-in vivo approach can elucidate specific bioactive ingredients and mechanisms underlying drug-diet interactions.
Ongoing and future studies from this National Institutes of Health-funded program will compose a framework for developing rigorous guidelines for prospective evaluation of drug-diet interactions. Human-derived in vitro systems will be used to identify individual bioactive constituents and to recover robust parameters associated with absorptive permeability and enteric CYP3A or OATP inhibition by single constituents and the natural mixture. The in vitro parameters recovered will be used to develop in silico models to predict the magnitude of effect of the dietary substance on systemic exposure to a model drug, informing clinical study design. Finally, accuracy of the in silico models will be evaluated in proof-of-concept clinical studies. The information gained in this effort will further leverage existing knowledge of genetic and non-genetic factors that determine drug response, and will progress towards the long-term goal of providing firm information to clinicians for managing drug-diet interactions appropriately.