Separating host and microbiome contributions to drug pharmacokinetics and toxicity

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6427
• Main Authors: Zimmermann, Michael, Zimmermann-Kogadeeva, Maria, Wegmann, Rebekka, Goodman, Andrew L
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 08-02-2019
• 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 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; Toxicity; Xenobiotics
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aat9931

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.