Separating host and microbiome contributions to drug pharmacokinetics and toxicity

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6427; p. 600
• Main Authors: Zimmermann, Michael, Zimmermann-Kogadeeva, Maria, Wegmann, Rebekka, Goodman, Andrew L.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 08.02.2019; The American Association for the Advancement of Science
• Subjects: Absorption; Animal models; Animal tissues; Animals; Antidepressants; Antiviral agents; Bacteroides thetaiotaomicron - enzymology; Bacteroides thetaiotaomicron - genetics; Benzodiazepines; Bioavailability; Biocompatibility; Biological Availability; Biotransformation; Bromodeoxyuridine - analogs & derivatives; Bromodeoxyuridine - pharmacokinetics; Bromodeoxyuridine - toxicity; Clonazepam; Clonazepam - pharmacokinetics; Compartments; Computer applications; Computer simulation; Conversion; Digestive system; Drug efficacy; Drug metabolism; Drugs; Effectiveness; Enzymes; Exposure; Food; Gastrointestinal Microbiome; Gastrointestinal tract; Genetic transformation; Genetics; Germ-Free Life; Germfree; Gnotobiotic; Gnotobiotics; Health services; In vivo methods and tests; Intestinal microflora; Intestine; Kinetics; Medical treatment; Metabolism; Metabolites; Mice; Microbiomes; Microbiota; Microorganisms; Narcotics; Nucleoside analogs; Nucleosides; Organic chemistry; Oxidation; Pharmacokinetics; Pharmacology; Physiological effects; RESEARCH ARTICLE SUMMARY; Toxicity; Xenobiotics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aat9931

Anything humans swallow is exposed to the foraging and transforming activities of the gut microbiota. This applies to therapeutic drugs as well as food components and can be a major source of interpersonal variation in drug efficacy and toxicity. Zimmermann et al. found that individual drug responses depend on the genetics of an individual's microbiota. They explored the metabolism of nucleoside drugs (which are used as antivirals and antidepressants) in mice inoculated with a variety of mutant microbiota. They then modeled the pharmacokinetics in different body compartments and identified the host and microbe contributions. In some individuals, up to 70% of drug transformation can be ascribed to microbial metabolism. Science , this issue p. eaat9931 Genetic manipulation of drug metabolism in human gut commensal bacteria resolves host and microbiome contributions. 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 is challenging, particularly in cases where host and microbiome perform the same metabolic transformation. We combined gut commensal genetics with gnotobiotics to measure brivudine drug metabolism across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by these measurements, we built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure, as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics. Clonazepam studies illustrate how this approach disentangles microbiome contributions to metabolism of drugs subject to multiple metabolic routes and transformations.