Contribution of the Gut Microbiome to Drug Disposition, Pharmacokinetic and Pharmacodynamic Variability

Abstract

The trillions of microbes that make up the gut microbiome are an important contributor to health and disease. With respect to xenobiotics, particularly orally administered compounds, the gut microbiome interacts directly with drugs to break them down into metabolic products. In addition, microbial products such as bile acids interact with nuclear receptors on host drug-metabolizing enzyme machinery, thus indirectly influencing drug disposition and pharmacokinetics. Gut microbes also influence drugs that undergo enterohepatic recycling by reversing host enzyme metabolic processes and increasing exposure to toxic metabolites as exemplified by the chemotherapy agent irinotecan and non-steroidal anti-inflammatory drugs. Recent data with immune checkpoint inhibitors demonstrate the impact of the gut microbiome on drug pharmacodynamics. We summarize the clinical importance of gut microbe interaction with digoxin, irinotecan, immune checkpoint inhibitors, levodopa, and non-steroidal anti-inflammatory drugs. Understanding the complex interactions of the gut microbiome with xenobiotics is challenging; and highly sensitive methods such as untargeted metabolomics with molecular networking along with other in silico methods and animal and human in vivo studies will uncover mechanisms and pathways. Incorporating the contribution of the gut microbiome to drug disposition, pharmacokinetics, and pharmacodynamics is vital in this era of precision medicine.

Fig. 1

Pathway of an orally administered drug. When a drug is administered orally (1), it encounters gut microbes, cytochrome P450 (CYP) enzymes, and transporters (TRP) such as P-glycoprotein (P-gp) in the small and large intestine. Some drug will be lost in the feces in these processes. The drug that survives the small intestine will then travel through the portal vein to the liver where it encounters more CYPs and TRP and more drug may be lost to metabolism (2). Some drugs undergo enterohepatic recycling in which drug conjugates are transported from the liver back to the intestine where they encounter microbes, CYP, and TRP again. The amount of drug that enters the systemic circulation is a fraction of what was originally ingested (3). ATP adenosine triphosphate