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
inactivation, a metabolic activity of the human anaerobic gut flora. Gut. 30(7): 971-7.                                                                            Lindenbaum J, Rund D G, Butler Jr. V P, Tse-Eng. D and Saha, J R. (1981). Inactivation of digoxin by gut flora: reversal by antibiotic therapy. N. Engl. J. Med.305. 789-794.

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
significant host-microbiome metabolic interaction affecting human drug metabolism.
Proc Natl Acad Sci USA. 106(34): 14728-33.

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.
Delgado S, Ruas-Madiedo P, Suarez A, et al. (2006) Interindividual differences in microbial counts and biochemical-associated variables in the feces of healthy Spanish adults. Dig Dis Sci 51(4): 737-43.

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

http://www.ncbi.nlm.nih.gov/pubmed/2358251

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

http://www.ncbi.nlm.nih.gov/pubmed/4960684

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

http://www.ncbi.nlm.nih.gov/pubmed/3055224

          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

http://www.ncbi.nlm.nih.gov/pubmed/3055224         

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