Editors' ChoiceCardiology

Drugs and Bugs

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Science Translational Medicine  14 Aug 2013:
Vol. 5, Issue 198, pp. 198ec135
DOI: 10.1126/scitranslmed.3007183

Digoxin is a cardiac glycoside used to treat heart disease and is one of the oldest medicines in the cardiologist’s arsenal. Derived from the foxglove plant, digoxin has been used since the 18th century for the treatment of “dropsy,” or systolic heart failure, as contemporary cardiologists know it. Digoxin has a well-established role in managing the symptoms of heart failure, although many cardiologists limit the prescribed dose because of the drug’s narrow therapeutic index. Individuals with elevated concentrations of circulating digoxin are at risk for adverse events, including slow heart rates and cardiac-rhythm disturbances that can be fatal. But clinicians have poor tools with which to identify individuals who are highest risk of developing adverse events as a result of digoxin toxicity. Although age, gender, and kidney function are currently used to guide digoxin dosing, there remains a large amount of interindividual variability in serum digoxin concentrations. As a consequence, digoxin remains a frequently cited cause of emergency hospitalizations resulting from adverse drug events in older adults.

For nearly three decades, enteric flora have been known to metabolize digoxin into inactive metabolites, and the coadministration of antibiotics increases serum digoxin concentrations. However, the mechanism underlying this drug-drug interaction was not known until now. New work by Haiser et al. dissects the process by which a specific strain of the human bacterium Eggerthella lenta metabolizes digoxin into an inactive metabolite in the digestive tract. This conversion reduces the amount of active digoxin that enters the systemic circulation.

By using RNA sequencing of strains of E. lenta that were exposed to digoxin, the authors identified a bacterial enzyme similar to bacterial cytochromes that is encoded by the cgr gene (for cardiac glycoside reductase) and is induced by digoxin. The genomes of other E. lenta strains do not encode cgr and, as a consequence, are incapable of metabolizing digoxin into its inactive metabolite. By introducing either the metabolizing type of E. lenta or other, nonmetabolizer E. lenta strains into mice, the authors were able to adjust the mice’s digoxin-metabolizing capabilities. Last, by studying human subjects with variable digoxin-metabolizing capabilities, the authors demonstrated a strong correlation between fecal amounts of digoxin-metabolizing E. lenta DNA and the capability to metabolize digoxin. The authors termed the ratio of cgr to E. lenta ribosomal DNA the “cgr ratio.” Individuals with low cgr ratios are predicted to metabolize digoxin incompletely, display high serum concentrations of digoxin, and be at highest risk for digoxin toxicity.

The authors also demonstrated that in mice, a high-protein diet can inhibit cgr expression through the delivery of arginine, which is used by E. lenta as a source of nitrogen, carbon, and energy, thus inhibiting the metabolic capacity of these mice and increasing serum digoxin concentrations. Therefore, Haiser et al. have identified two potential therapeutic routes by which digoxin metabolism can be manipulated in vivo: supplementation of the gut microbiome with a metabolizing strain of E. lenta or the addition of a high-protein diet. The cgr ratio could be used to monitor the effects of any intervention so as to ensure that patients receiving digoxin have adequate enteric microbial communities to metabolize digoxin and avoid its toxic effects.

H. J. Haiser et al., Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013). [Abstract]

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