创作:小肠 审核:小肠 02月11日
Science [IF:41.058]

Separating host and microbiome contributions to drug pharmacokinetics and toxicity


02-08, Article, 10.1126/science.aat9931more

INTRODUCTION: The gut microbiota is implicated in the metabolism of many medical drugs, with consequences for interpersonal variation in drug efficacy and toxicity. However, quantifying microbial contributions to drug metabolism in vivo is challenging, particularly in cases where host and microbiome perform the same metabolic transformation. A quantitative understanding of the physiological, chemical, and microbial factors that determine microbiome contributions to drug metabolism could help explain interpersonal variability in drug response and provide opportunities for personalized medical treatments.
RATIONALE: To experimentally dissect microbiome and host drug metabolism, we combined gut commensal genetics with gnotobiotics to measure metabolism of the nucleoside analog brivudine (BRV) across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by these measurements, we built a pharmacokinetic model to quantitatively predict microbiome contributions to systemic drug and metabolite exposure. Model simulations evaluate the impact of oral bioavailability, host and microbial drug-metabolizing activity, metabolite absorption, and intestinal transit on microbiome contributions to drug metabolism. To test the general applicability of this approach, we performed additional studies with the benzodiazepine clonazepam to quantitatively untangle microbiome contributions to metabolism of a drug subject to multiple metabolic routes and transformations.
RESULTS: We demonstrate BRV conversion to hepatotoxic bromovinyluracil (BVU) by both mammalian and microbial enzymes and reduced systemic BVU exposure in germ-free mice, suggesting a microbiome contribution to serum BVU. Drug conversion assays with axenic cultures and an arrayed transposon library identified BRV-metabolizing gut bacteria and responsible gene products. This enabled us to establish mouse models that are isogenic except for a single bacterial gene responsible for microbial BRV metabolism. Administration of oral BRV and quantification of drug and drug metabolite kinetics in different body compartments provided the data to develop a host-microbiome pharmacokinetic model. This model accurately predicts serum BVU exposure and quantifies host and microbiome contributions to its pharmacokinetics. Model simulations revealed how drug, host, and microbial parameters affect host-microbiome drug metabolism. To test whether this approach applies to other microbiome-metabolized drugs, we quantified microbiome and host contributions to the metabolism of sorivudine, which is structurally related to BRV but is metabolized to BVU at different rates by both host and microbiome. We also quantified microbiome and host contributions to serum clonazepam metabolites produced through oxidation, nitroreduction, glucuronidation, and enterohepatic cycling.
CONCLUSION: This study provides an experimental and computational strategy to untangle host and microbial contributions to drug metabolism. Quantitative understanding of the interplay between host and microbiome-encoded metabolic activities will clarify how nutritional, environmental, genetic, and galenic factors affect drug metabolism and could enable tailored intervention strategies to improve drug responses. This approach could also be adapted to other xenobiotics, food components, and endogenous metabolites.

First Authors:
Michael Zimmermann,Maria Zimmermann-Kogadeeva

Correspondence Authors:
Andrew L Goodman

All Authors:
Michael Zimmermann,Maria Zimmermann-Kogadeeva,Rebekka Wegmann,Andrew L Goodman