Updated Gut Pharmacomicrobiomics Data
Drug | CID | Role | Function | Effect of microbiota on the clinical outcome | Reference | PMID | Year | NCBI Link |
Baicalin | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=64982 | Potential antioxidant, anti-inflammatory and liver tonic | Gut microbiota normally hydrolyze baicalin into its corresponding aglycone baicalein which is readily absorbable and subject to re-conjugation following absorption. Absence of gut microbiota in germfree rats has resulted in lower levels of baicalin in plasma following oral administration. | Potentiate clinical effect | Akao T, Kawabata K, Yanagisawa E, Ishihara K, Mizuhara Y, Wakui Y, Sakashita Y and Kobashi K (2000). Baicalin, the predominant flvone glucuronide of scutellarie radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J. Pharm. Pharmacol. 52(12):1563-8 | 11197087 | 2000 | http://www.ncbi.nlm.nih.gov/pubmed/11197087 |
Digoxin | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2724385 | Cardiac glycoside | Altered concentration of E. lentum between populations has been correlated with the difference in the reduced metabolite concentration. Comparing the reduced digoxin metabolite profiles between North Americans and Southern Indians showed 36% and 13.7% respectively which has been correlated with altered concentrations of E. lentum between the two populations (Mathan et al, 1989). Furthermore, a recent case-control study, has showed that concomitant administration of digoxin and erythromycin or tetracycline has resulted in digoxin intoxication. Accordingly, it is recommended to avoid the concurrent use of both medications. The authors of the study proposed the reduction in E. lentum among the potential underlying causes for this toxicity (Lindenbaum et al, 1981). | Potentiated effect and toxicity | Mathan VI, Wiederman J, Dobkin JF, et al. (1989). Geographic differences in digoxin | 2759492 | 1989 | http://www.ncbi.nlm.nih.gov/pubmed/2759492 |
Chlorogenic acid | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1794427 | Antioxidant | Gut microbiota metabolize chlorogenic acid in to 3- hydroxy cinnamic acid and 3-(hydroxyl phenyl) propionic acid which are subject to phase II conjugation followed by excretion in urine. In absence of gut microbiota, chlorogenic acid is metabolized to benzoic acid which in turn is conjugated with glycine yielding hippuric acid. This has been verified by the absence of these metabolites upon administration of antibiotics and in germ free rats. Gonthier et al have concluded that the bioavailability of chlorogenic relies on its metabolism by gut microbiota. Variation in the concentrations of chlorogenic acid metabolites was found among rat population. H1NMR spectroscopy showed that elevated concentration of the metabolites in urine was accompanied by low hippuric acid concentration in a rat subpopulation that is similar in terms of species, genetic background and conditions of maintenance to the other group of rats (Gavaghan et al, 2001). This suggests the difference in gut microbiota between the two rats populations. Based on the results retrieved by Gonthier et al, the elevated concentration of the metabolites will result in turn in increased bioavailability and thereby augmented efficacy. | Potentiate the clinical effect | Gonthier M-P, Verny M-A, Besson C, Remesy C and Scalbert A. (2003). Chlorogenic acid bioavailability largely depends on its metabolism by the gut microflora in rats. The Journal of Nutrition. 133: 1853-1859. | 12771329 | 2003 | http://www.ncbi.nlm.nih.gov/pubmed/12771329 |
Acetaminophen | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1983 | analgesic and antipyretic | Acetaminophen toxicity is associated with elevated levels of p-cresol which is produced by some bacterial community owing to the competition of p-cresol with acetaminophen on the o-sulfonation metabolism. Thereby, it has been suggested to establish the assessment of microbiome activity as a guideline prior to the administration of acetamniophen. | Exaggerated clinical effect and toxicity | Clayton T A, Baker D, Lindon J C, et al. (2009). Pharmacometabonomic identification of a | 19667173 | 2009 | http://www.ncbi.nlm.nih.gov/pubmed/19667173 |
Soy-derived phytoestrogens | Xenoestrogens | Some microbial communities in the gut produce active metabolites from soy-derived phytoestrogens resulting in enhanced efficacy (Bowey et al, 2003). In addition, the phytoestrogens metabolites produced by gut microbiota are suggested to affect cytochrome P enzymes which are responsible for estrogen hydroxylation and therefore results in lower toxic events (Delgado et al, 2006). | According to the type of microbiota present, toxicity or lower action may result. | Bowey E, Adlercreutz H and Rowland I. (2003). Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats. Food Chem Toxicol 41(5): 631-6. | 12659715, 16614997 | 2003, 2006 | http://www.ncbi.nlm.nih.gov/pubmed/12659715 http://www.ncbi.nlm.nih.gov/pubmed/16614997 | |
(+)- catechin and (-)-epichatechins | Anti-oxidants | The effects of (+)-catechins and (-)-epicatechins on liver and intestinal enzymes have been reported to be different between germ free rats and rats with human gut flora. In germ free rats, (+)-catechins and (-)-epicatechins resulted in increase in the levels of liver CYP450 2C11 and (+) catechins caused elevation in the specific activity of liver UGT-Chloramphenicol. In addition, cytosolic GST levels has been reported to be increased in rats harbouring human gut flora upon the administration of (+)-catechins. However, in both germ free and human microbiota inoculated rats, (+)-catechins and (-)-epicatechins increased the specific activity of UGT-4-methyl umbelliferone in intestine. Furthermore, the specific activity of intestinal UGT-Chloramphenicol has been reported to be increased in rats inoculated with human microbiota. | Indirect potentiating/lowering effect on drug depending on the type of the drug co-administered, the metabolic pathway adapted and the effect of the resulting metabolite. | Lhoste E F, Ouriet V, Flinois J-P, Brezillion C., Magdalou J., Cheze C, Nugon-Baudon L. (2003). The human colonic microflora influences the alterations of xenobiotic-metabolizing enzymes by catechins in male F344 rats. Food and Chemocal Toxicology. 41:695-702 | 12659723 | 2003 | http://www.ncbi.nlm.nih.gov/pubmed/12659723 | |
Zonisamide | Anticonvulsant | Gut microbiota is central to the metabolism of zonisamide by reduction producing 2-sulfomoyacetylphenol. Upon measuring the level of this metabolite between conventional rats and germ-free rats, germ-free rats showed lower levels. This has been further confirmed by the incraese in the levels of 2-sulfomoyacetylphenol by re-inoculation of the germ-free rats with gut microbiota. | Lower the effect | Kitamura S, Sugihara K, Kuwasko M and Tatsumi K. (1997). The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J. Pharm. Pharmacol. 49: 253-256. | 9231340 | 1997 | http://www.ncbi.nlm.nih.gov/pubmed/9231340 | |
Metronidazole | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4173&loc=ec_rcs | Antibiotic | Comparison between metronidazole metabolites between germ-free rats and conventional rats showed the excretion of the metabolites by conventional rats only. Furthermore, the metabolites have been retrieved upon adding C. perfringens to metronidazole. | Lower the effect | Koch R L, Chrystal E J T, Beaulieu Jr. B B and Goldman P. (1979). Acetamide-a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 28: 3611-3615. | 231450 | 1979 | http://www.ncbi.nlm.nih.gov/pubmed/231450 |
Sorivudine | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5282192&loc=ec_rcs | Antiviral | A toxic interaction has been reported in 18 Japanese people upon concomitant administration of sorivudine orally and 5-fluorouracil (5-FU). Bacteroids species 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 (Nakayama et al, 1997). This has been further confirmed when germ-free rats showed significantly lower BVU levels in both urine and blood (Ashida et al, 1993). | Toxicity | Nakayama H, Kinouchi T, Kataoka K, Akimoto S, Matsuda Y and Ohinishi Y. (1997). Intestinal anaerobic bacteria hydrolyse sorivudine producing the high blood concentration (E)-5-(2-bromovinyl) uracil (BVU) that increases the level and toxicity of 5-fluorouracil. Pharmacogenetics.7:35-43. Ashida N, Ljichi K, Watanabe Y and Machida H. (1993). Metabolism of 5'-ether prodrugs of 1-ᵦ-d-arabinofuranosyl-e-5(2-bromovinyl)uracil in rats. Biochem Pharmacol. 46:2201-2207. | 9110360, 8274153 | 1997, 1993 | |
Chloramphenicol | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5959&loc=ec_rcs | Antibiotic | A small no. of population harboring coliforms have been reported to generate toxic metabolites for chloramphenicol. | Toxicity | Holt R. (1967). The bacterial degradation of chloramphenicol. Lancet. 1: 1259 | 1967 | ||
Flucytosine | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3366&loc=ec_rcs | Antifungal | Patients who have received antibiotics showed lowered metabolism of flucytosine to 5-FU. | Potentiate effect | Vermes E, Kuijiper E J., Guchelaar H J and Dankret J. (2003). An in vitro study on the active conversion of flucytosine to fluorouracil by the microorganisms in the human intestinal microflora. Chemotherapy. 49:17-23. | 12714804 | 2003 | http://www.ncbi.nlm.nih.gov/pubmed/12714804 |
Heterocyclic aromatic amines (HAAs) | Carcinogenic/Mutagenic | HAAs are pro-mutagenic compounds which are known to be carcinogenic to rats and mice. They are originally derived from cooking of proteins. Normally upon ingestion of cooked protein, human liver enzymes CYP450 IA1 and IA2 activate these compounds to the active mutagenic forms. However, metabolism by gut microbiota is an inevitable step prior to the liver metabolism since these compounds exist in conjugates which required to be broken to facilitate their uptake by the enterohepatic circulation. Thereby, gut microbiota metabolize these compounds to yield unconjugated mutagen metabolites that are detectable in urine and stool. | The role of gut microbiota in the metabolism of HAAs has been assessed in a study through comparing the excretion profiles HAAs mutagenic metabolites in urine and stools of both conventional and germ free rats upon feeding with fried meet. HPLC analysis showed higher levels of excreted mutagens in conventional rats than in germ free rats. Furthermore, on contrary to conventional rats, conjugated mutagens were retrieved from the urine and stool of germ free rats. The effect of elevated active mutagens metabolites was reported to be significantly higher in conventional rats than germ free rats. Conventional rats have shown elevated activity of ethoxyresorufin-O-deethylase (EROD) which is a CYP 450 dependent enzyme responsible for the biotransformation of HAAs and is known to be increased in the small intestine upon ingestion of fried meat. Thus, the authors of this study concluded that the intestinal microbiota plays a central role in metabolism and thereby, the response to mutagens through enhancing the activity of CYP 450 responsible for the activation of mutagens. | Overvick, E., Midtvedt, T., and Gustafsson, J. (1990) Mutagen execretion and cytochrome P-450- dependent activity in germ free and conventional rats fed a diet containing fried meat. Fd Chem Toxic. 28 (4): 253-261 | 2358251 | 1990 | ||
Cycasin | 5459896 | Toxic Glycoside | Gut microbiota hydrolyze cycasin into a carcinogenic derivative known as methylazoxymethanol. | Toxic effect | Spatz, M., Smith, D. W., McDaniel, E. G. and Lageur, G. L. (1967). Role of intestinal microorganisms in determining cycasin toxicity. Proc. Soc. Exp. Biol. Med. 124(3): 691-7. | 4960684 | 1967 | |
Rutin | 5280805 | A quercetin glucoside with angio-protective effects. | Several gut anaerobes such as Bacteriodes uniformans, Bacteroides ovatus, and Butrivibrio sp. hydrolyze the dietary rutin into its corresponding quercetin aglycone and polyphenols. Interestingly, the release of both the free quercetin aglycone and the phenolic metabolites underlies the mutagenic and the further inhibition of platelet aggregation respectively. The free quercetin aglycone responsible for the mutagenic effect as confirmed by the Ames test where rutin didn't trigger mutations in the absence ᵦ-glycosidase activity. Furthermore, rutin has been reported to increase the activity of ᵦ-glycosidase in a dose- dependent fashion in the cecum and liver S9 fractions of mice fed with diets upon feeding rats with diets containing rutin ranging from 0 to 2.5%w/w. Accordingly, the administration of rutin has been correlated with the increase of mutagenic activity of other glycosides with mutagenic aglycone component. This has led to the premise that this increase in glycosidic activity would further increase the release of querectin. However, the activation of querectin was decreased in rats fed with rutin in contrast to the free aglycones of other mutagens such as 2-amino-3-methylimidazo [4,5-f] quinoline (IQ), 2-amino-3,4-dimethylimidazo [4,5-f] quinoline (MeIQ), and 2-amino-3,8-dimethylimidazo-[4,5-f] quinoxaline (MeIQx). Regarding the phenolic metabolites, both the 3,4 dihyroxyphenylacetic acid and 4-hydroxyphenylacetic acid have been correlated with increased prevention of platelet aggregation, together with, the presumable inhibition of NADPH oxidase. | Indirect mutagenic effect | Rowland, I. R. (1988). Interactions of the Gut Microflora and the Host in Toxicology. Toxicol Pathol. 16: 147. DOI: 10.1177/019262338801600207 | 3055224 | 1988 | |
Aflatoxin B1 | 186907 | Carcinogenic mycotoxins | Rats with conventional gut microbiota have shown two-fold increase in the aflatoxin concentration in S9liver fraction. Additionally, upon an attempt to assay the effect of the gut microbiota on the mutagenic effect of aflatoxin employing an in-vivo modified Ames test with Salmonella typhimurium TA98 as a mutagenicity indicator and comparing conventional and germfree rats, the rats with conventional gut microbiota have displayed higher number of Salmonella typhimurium TA98 mutants. | Potentiated toxic effects | Rowland, I. R. (1988). Interactions of the Gut Microflora and the Host in Toxicology. Toxicol Pathol. 16: 147. DOI: 10.1177/019262338801600207 | 3055224 | 1988 | |
Catechins and Epicatechins | http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9064&loc=ec_rcs http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=72276&loc=ec_rcs | Antioxidants | The effects of (+)-catechins and (-)-epicatechins on liver and intestinal enzymes have been reported to be different between germ free rats and rats with human gut flora. In germ free rats, (+)-catechins and (-)-epicatechins resulted in increase in the levels of live r CYP450 2C11 and (+) catechins caused elevation in the specific activity of liver UGT-Chloramphenicol. In addition, cytosolic GST levels has been reported to be increased in rats harbouring human gut flora upon the administration of (+)-catechins. However, in both germ free and human microbiota inoculated rats, (+)-catechins and (-)-epicatechins increased the specific activity of UGT-4-methyl umbelliferone in intestine. Furthermore, the specific activity of intestinal UGT-Chloramphenicol has been reported to be increased in rats inoculated with human microbiota. | Indirect effect through enzymatic induction | Lhoste E F, Ouriet V, Flinois J-P, Brezillion C., Magdalou J., Cheze C, Nugon-Baudon L. (2003). The human colonic microflora influences the alterations of xenobiotic-metabolizing enzymes by catechins in male F344 rats. Food and Chemocal Toxicology. 41:695-702 | 12659723 | 2003 | http://www.ncbi.nlm.nih.gov/pubmed/12659723 |