Can changes to the gut microbiome alter the effectiveness of pain relievers? New research is suggesting this is possible, and even likely. In research published in Nature Scientific Reports, study authors examined how changes in the bacterial composition in the gastrointestinal system can influence not only side effects of drugs ingested, but also may compromise how well they work for the purposes prescribed.

Recognizing that many factors can influence the metabolism of medications, lead author, Michael Malfatti, LLNL, and his team explored the impact of an alteration of the gut microbiology of C57Bl/6 mice on both the pharmacokinetics (PK) and the biodistribution of the common OTC analgesic, acetaminophen. Using antibiotics including amoxicillin, ciprofloxacin, or a combination of ampicillin with neomycin to disrupt the gut microbiome, the research team examined the PK profiles, including elimination, in the subject mice. Although they recognize that many factors can influence PK, the authors say “Much of the variation can be contributed to genetics, but environmental factors such as nutritional status, disease state, and gut bacterial composition can also profoundly influence the metabolic phenotype.”

The team highlighted their findings as statistically significant with plasma concentration of acetaminophen obtained after a single oral (100 mg/kg) dose of acetaminophen, administered to mice receiving placebo (control received water) or those receiving a 10-day course of antibiotics. The researchers reported the mean acetaminophen Cmax for the mice that received the antibiotics as 80.9 µg/ml for those receiving amoxicillin and 62.8 mg/mL for mice receiving ampicillin/neomycin, compared with 105.6 µg/ml in the control group. 

The team noted that there was not a significant difference in the acetaminophen plasma concentrations in mice that received ciprofloxacin compared with controls. The mean half-life varied between groups, with the mice receiving the ampicillin/neomycin combination reported as 0.66 hour, which was nearly 1.5 times longer than the controls, which reported a 0.46-hour half-life. Amoxicillin- or ciprofloxacin-treated mice had no change in the half-life.

The team concluded that their findings reinforce the importance of the composition of the gut microbiome as “an essential consideration in determining the metabolic response of the host to xenobiotics” and that “manipulation of the gut microbiome can have consequences for drug disposition.” 

“These results suggest that exposure to amoxicillin or ampicillin/neomycin can alter the pharmacokinetics and metabolism of acetaminophen, and that these alterations could be due to changes in gut microbiome composition,” said Malfatti, who added, “Shifts in the composition of gut microbiota can disturb the balance of organisms, which can influence the biodisposition of orally administered drugs.”

The researchers highlight that in addition to one’s genetic composition, the individual’s microbiome must also be considered for optimal drug efficacy and when evaluating the response to pharmacological interventions.

Dr. Jepps concludes, “It still gets metabolized, but it happens elsewhere in the body, where the subsequent chemicals can cause an effect that wouldn't normally happen, if the drug was taken orally. Because we have identified the mechanism of how the side effect occurs, we believe we are able to offer a potential pharmaceutical design for a new kind of co-therapy: a type of paracetamol infused with another drug that prevents the drop in blood pressure.”

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