Insights from pharmacokinetic models of host-microbiome drug metabolism

ABSTRACT

Increasing evidence suggests a role of the gut microbiota in patients’ response to medicinal drugs. In our recent study, we combined genomics of human gut commensals and gnotobiotic animal experiments to quantify microbiota and host contributions to drug metabolism. Informed by experimental data, we built a physiology-based pharmacokinetic model of drug metabolism that includes intestinal compartments with microbiome drug-metabolizing activity. This model successfully predicted serum levels of metabolites of three different drugs, quantified microbial contribution to systemic drug metabolite exposure, and simulated the effect of different parameters on host and microbiota drug metabolism. In this addendum, we expand these simulations to assess the effect of microbiota on the systemic drug and metabolite levels under conditions of altered host physiology, microbiota drug-metabolizing activity or physico-chemical properties of drugs. This work illustrates how and under which circumstances the gut microbiome may influence drug pharmacokinetics, and discusses broader implications of expanded pharmacokinetic models.

KEYWORDS:

• Gut microbiota
• drug metabolism
• physiology-based pharmacokinetic modeling

Additional information

Funding

This work was supported by NIH grants GM118159, GM105456, the Center for Microbiome Informatics and Therapeutics, the Burroughs Wellcome Fund, and the HHMI Faculty Scholars Program to A.L.G. M.Z. received Early and Advanced Postdoc Mobility Fellowships from the Swiss National Science Foundation (P2EZP3_162256 and P300PA_177915, respectively) and a Long-Term Fellowship (ALTF 670-2016) from the European Molecular Biology Organization. M.Z.K. received an Early Postdoc Mobility Fellowship from the Swiss National Science Foundation (P2EZP3_178482).