Table 3 Role of gut microbiota in the metabolism of conventional first line therapies and over-the-counter (OTC) drugs

Acetaminophen {1983}

Analgesic and antipyretic

Competitive o-sulfonation between p-cresol, produced by some gut bacterial communities, and acetaminophen increases acetaminophen toxicity. Therefore, assessment of microbiome activity has been suggested as a guideline prior to the administration of acetamniophen.

Exaggerate clinical effect and toxicity

[43]

Chloramphenicol {5959}

Antibiotic

Some patients display bone marrow aplasia following the oral administration of chloramphenicol owing to the presence of coliforms that mediate the metabolic conversion of chloramphenicol to a toxic form known as p-aminophenyl-2-amin-1,2-propanediol.

Increase toxicity

[45]

Digoxin {2724385}

Cardiotonic

Altered concentration of Eggerthella lenta between populations affects the concentration of reduced digoxin metabolite. 36 % of North Americans vs. 13.7 % southern Indians were able to metabolize digoxin, a difference that was correlated with altered concentrations of E. lenta between the two populations. Concomitant administration of digoxin and erythromycin or tetracycline resulted in digoxin intoxication. Accordingly, it is recommended to avoid the concurrent use of both medications.

Potentiate both activity and toxicity

[8, 9]

Flucytosine {3366}

Antifungal

Patients who have received antibiotics showed lowered metabolic transformation of flucytosine (commonly known as 5-fluorocytosine) to 5-fluorouracil (5-FU).

Potentiate effect

[44]

Metronidazole {4173}

Antibiotic: antifungal and antimicrobial (against anaerobic microbes)

Bacteroides fragilis is among gut commensals, and its infection is commonly treated by metronidazole. A strain of B. fragilis that overexpresses recA was resistant to metronidazole in comparison to the wild-type strain. Inactivation of recA resulted in the increased sensitivity to metronidazole, and the B. fragilis recA mutants had more double strand breaks.

Provide resistance to the antimcrobial/antifungal effect

[46]

Metronidazole {4173}

Antibiotic: antifungal and antimicrobial (against anaerobic microbes)

Comparison of metronidazole metabolites between germfree rats and conventional rats showed the exclusive excretion of the metabolites by conventional rats. Those metabolites were retrieved upon adding Clostridium perfringens to metronidazole.

Lower the effect by activating metabolism

[13]

Sulfasalazine

Azodyes/Antibiotics

Salfasalazine is a prodrug that requires activation by azoreduction, mediated by intestinal bacteria, to result in sulfapyridine and 5-aminosalisylic acid. Patients who have undergone ileostomy had lower plasma levels of sulfapyridine than controls. Futhermore, antibiotic administration resulted in decrease of the azoreduction split. Intestinal microbiota mediate the clearance of both sulfapyridine and 5-aminosalisylic acid, where the decrease in acetylation rate is associated by increased side effects.

Activate the drug

[47]

Sulfinpyrazone {5342}

Azodyes/Antibiotics

The gut microbiota plays a major role in the azoreduction of sulfinpyrazone. Ilesotomy patients had dramatically lower levels of the sulfide form than controls (the area under the curve, AUC, for sulfide metabolite was 25-fold lower in the plasma in case of ileostomy patients).

Activate the drug

[47]

Sulindac {1548887}

Non steroidal anti-inflammatory drug (NSAID)

Sulindac is a prodrug that undergoes reductive metabolism by gut microbiota and liver enzymes into an active sulfone metabolite. Patients with ileostomy exhibited half the AUC following 12 hours of oral administration of 200 mg dose.

Activate the drug

[47, 48]

Sorivudine {5282192}

Antiviral

A toxic interaction was reported in 18 Japanese people upon concomitant oral administration of sorivudine and 5-FU. Bacteroides sp. are responsible for this toxicity owing to their production to (E)-5-(2-bromovinyl) uracil (BVU) metabolite which in turn deactivates dihydropyrimidine dehydrogenase (DPD) responsible for the metabolism of 5-FU. Germfree rats had significantly lower BVU levels in both urine and blood.

Increase toxicity

[49, 50]

Zonisamide {5734}

Anticonvulsant

Gut microbiota is central to the metabolism of zonisamide by reduction producing 2-sulfomoyacetylphenol. Germfree rats had lower levels of this metabolite, and its levels were increased after those rats were inoculated with gut microbiota.

Lower the effect

[51]