Reduction | Prontosil (Gingell et al., 1971) | Azoreductase enzymes | Activation of azo-bond containing prodrug to sulfanilamide |
| Neoprontosil (Gingell et al., 1971) | | |
| Sulfasalazine (Peppercorn and Goldman, 1972) | | Activation of azo-bond containing prodrug to 5-aminosalicylic acid |
| Balsalazide (Chan et al., 1983) | | |
| Olsalazine (Wadworth and Fitton, 1991) | | |
| Nitrazepam (Rafii et al., 1997) | Nitroreductase | Cometabolism of nitrazepam produces 7-acetylaminonitrazepam responsible for teratogenic activity: step 1, nitroreduction of nitrazepam to 7-aminonitrazepam by gut microbiota; and step 2, 7-aminonitrazepam is converted to 7-acetylaminonitrazepam in the liver |
| Clonazepam (Elmer and Remmel, 1984) | Not reported | Nearly complete reduction to 7-aminoclonazepam |
| Misonidazole (Koch et al., 1980) | Not reported | Reduction to 1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol |
| Omeprazole (Watanabe et al., 1995) | Not reported | In vitro reduction by gut microbiota to omeprazole sulfide metabolite. However, there was no alteration of oral in vivo pharmacokinetics because omeprazole is fully absorbed before reaching the hindgut |
| Sulfinpyrazone (Strong et al., 1987) | Not reported | Reduction to sulfinpyrazone sulfide metabolite (solely by gut microbiota) |
| Sulindac (Strong et al., 1987) | Not reported | Reduction to sulindac sulfide metabolite |
| Digoxin (Lindenbaum et al., 1981; Haiser et al., 2013) | Eggerthella lenta | Reduction to inactive metabolites (e.g., dihydrodigoxin or dihydrodigoxigenin) by gut microbiota reduce therapeutic efficacy |
| Zonisamide (Kitamura et al., 1997) | Clostridium sporogenes | Reduction to 2-sulphamoylacetylphenol |
| Metronidazole (Koch et al., 1979) | Clostridium perfringens | Reduction to N-(2-hydroxyethyl)-oxamic acid and acetamide |
Hydrolysis | Lactulose (Sahota et al., 1982) | Lactobacillus, Bacteroides, and Clostridium | Therapeutic activity depends on its metabolism by intestinal bacteria to form lactic and acetic acids |
| Sorivudine (Okuda et al., 1998) | Bacteroides species (e.g., Bacteroides eggerthii and Bacteroides vulgatus) | A major metabolite of sorivudine, (E)-5-(2-bromovinyl)uracil, generated from microbial metabolism of the drug was found to inactivate a key hepatic enzyme involved in the metabolism of 5-fluorouracil. Coadministration of sorivudine and 5-fluorouracil resulted in drug interactions that led to death |
Deconjugation of drugs excreted in bile as inactive conjugates | Digitoxin (Volp and Lage, 1978) | β-glucuronidase | Hydrolysis of glucuronide |
| Indomethacin (Saitta et al., 2014) | | Hydrolysis of glucuronide of indomethacin release the aglycone which leads to gastrointestinal toxicity |
| Morphine (Walsh and Levine, 1975) | | Hydrolysis of glucuronide |
| Irinotecan (Roberts et al., 2013) | | Hydrolysis of SN-38 glucuronide of irinotecan (prodrug) release SN-38 in the intestines, which leads to gastrointestinal toxicity |
Removal of succinate group | Succinylsulfathiazole (Sousa et al., 2008) | Not reported | Activation of prodrug to sulfathiazole |
Dehydroxylation | l-Dopa (Goldin et al., 1973) | Not reported | Alteration of l-dopa pharmacokinetics by gut microbiota metabolism to form m-tyramine and m-hydroxyphenylacetic acid |
Acetylation | 5-Aminosalicylic acid (Dull et al., 1987; Deloménie et al., 2001) | N-acetyltransferase | Acetylation to form acetylated 5-aminosalicylic acid |
Deacetylation | Phenacetin (Smith and Griffiths, 1974) | Not reported | Formation of p-phenetidin from deacetylation reaction is correlated with toxicities such as methemoglobinemia and nephritis |
Cleavage of N-oxide bond | Ranitidine (Basit and Lacey, 2001) | Not reported | Susceptible to N-oxide bond cleavage by gut bacteria |
| Nizatidine (Basit et al., 2002) | Not reported | Susceptible to N-oxide bond cleavage by gut bacteria |
Proteolysis | Insulin (Tozaki et al., 1997) | Not reported | Susceptible to proteolysis |
| Calcitonin (Tozaki et al., 1997) | Not reported | Susceptible to proteolysis |
Denitration | Glyceryl trinitrate (Abushamat, 1993; Sousa et al., 2008) | Not reported | Generate glyceryl-1,3-dinitrate, glyceryl-1,2-dinitrate, glyceryl-1-mononitrate, and glyceryl-2-mononitrate |
| Isosorbide dinitrate (Sousa et al., 2008) | Not reported | Generate isomeric mononitrates and isosorbide |
Amine formation and hydrolysis of amide linkage | Chloramphenicol (Holt, 1967) | Not reported | Metabolized to metabolites such as p-aminophenyl-2-amino-1,3-propanediol. Aplasia of the marrow, the most serious complication of chloramphenicol, has been proposed to be attributable to the activity of the intestinal microbiota |
Thiazole ring-opening | Levamisole (Shu et al., 1991) | Bacteroides and Clostridium species | Generate levametabol-I, levametabol-I, and levametabol-III metabolites |
Isoxazole scission | Risperidone (Meuldermans et al., 1994) | Not reported | Scission of the isoxazole in the benzisoxazole ring system of risperidone is a major metabolic pathway contributed by the gut microbiota |
N-Demethylation | Methamphetamine (Caldwell and Hawksworth, 1973) | Not reported | Converted to amphetamine by gut microbiota. May be inconsequential to humans since the parent drug is quite efficiently absorbed in the upper gastrointestinal tract |
Competition of microbial metabolite for phase II drug clearance | Acetaminophen (Clayton et al., 2009) | Bacteria like Clostridium difficile are p-cresol producers | High predose levels of microbial metabolite p-cresol compete for clearance by hepatic sulfotransferase and diminish the host’s metabolic capacity for phase II sulfonation of acetaminophen |
Competition of microbial metabolite for hepatic uptake of drug | Simvastatin (Kaddurah-Daouk et al., 2011) | Bacteria like Lactobacillus are involved in production of coprostanol | Microbially derived secondary bile acids may compete with simvastatin for hepatic uptake by SLCO1B1 transporters, thereby affecting the pharmacokinetics and pharmacodynamics of simvastatin, and increasing the risk of myopathy |