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Reviews

The influence of gut microbiota on drug metabolism and toxicity

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Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers

•This review provides an overview of gut microbiota involvement in disease development and hypothesizes that gut microbiota could be a potential drug target.

••This review systemically summarized the gut microbiota modulation on many natural products and synthetic drugs.

  • Rajilic-Stojanovic M, Smidt H, De Vos WM. Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol. 2007;9(9):2125–2136.
  • Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012;4(1):16.

•This paper discussed the complicated relationship between host and gut microbes, and coined the term of “pharmacomicrobiomics”.

••In this paper, the authors summarized the roles of gut microbiota in xenobiotic metabolism with some important examples.

  • Clayton TA, Baker D, Lindon JC, et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci USA. 2009;106(34):14728–14733.
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  • Yoo DH, Kim IS, Van Le TK, et al. Gut microbiota-mediated drug interactions between lovastatin and antibiotics. Drug Metab Dispos. 2014;42(9):1508–1513.

•This paper provides evidence for gut microbial impacts on drug metabolism, such as for lovastatin.

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  • Shim SB, Kim NJ, Kim DH. Beta-glucuronidase inhibitory activity and hepatoprotective effect of 18 beta-glycyrrhetinic acid from the rhizomes of Glycyrrhiza uralensis. Planta Med. 2000;66(1):40–43.
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  • Takeno S, Sakai T. Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction. Teratology. 1991;44(2):209–214.
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  • Lavrijsen K, Van Dyck D, Van Houdt J, et al. Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans. Drug Metab Dispos. 1995;23(3):354–362.
  • Tralau T, Sowada J, Luch A. Insights on the human microbiome and its xenobiotic metabolism: what is known about its effects on human physiology? Expert Opin Drug Metab Toxicol. 2015;11(3):411–425.
  • Li H, Jia W. Cometabolism of microbes and host: implications for drug metabolism and drug-induced toxicity. Clin Pharmacol Ther. 2013;94(5):574–581.

••This review discussed the cometabolism between host and microbiota, and summarized the drugs metabolized by gut microbiota.

  • Nakayama H, Kinouchi T, Kataoka K, et al. Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil. Pharmacogenetics. 1997;7(1):35–43.
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  • Trinh HT, Joh EH, Kwak HY, et al. Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice. Acta Pharmacol Sin. 2010;31(6):718–724.
  • Kang MJ, Ko GS, Oh Do G, et al. Role of metabolism by intestinal microbiota in pharmacokinetics of oral baicalin. Arch Pharm Res. 2014;37(3):371–378.
  • Matthies A, Clavel T, Gutschow M, et al. Conversion of daidzein and genistein by an anaerobic bacterium newly isolated from the mouse intestine. Appl Environ Microbiol. 2008;74(15):4847–4852.
  • Renouf M, Hendrich S. Bacteroides uniformis is a putative bacterial species associated with the degradation of the isoflavone genistein in human feces. J Nutr. 2011;141(6):1120–1126.
  • Akao T, Kida H, Kanaoka M, et al. Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb-1 from Panax ginseng. J Pharm And Pharmacol. 1998;50(10):1155–1160.
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  • Di L. The role of drug metabolizing enzymes in clearance. Expert Opin Drug Metab Toxicol. 2014;10(3):379–393.
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  • Lee SH, An JH, Lee HJ, et al. Evaluation of pharmacokinetic differences of acetaminophen in pseudo germ-free rats. Biopharm Drug Dispos. 2012;33(6):292–303.
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  • Possamai LA, McPhail MJ, Khamri W, et al. The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity. Liver Int. 2015;35(3):764–773.
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  • Wilson ID. Drugs, bugs, and personalized medicine: pharmacometabonomics enters the ring. Proc Natl Acad Sci USA. 2009;106(34):14187–14188.
  • Kajinami K, Akao H, Polisecki E, et al. Pharmacogenomics of statin responsiveness. Am J Cardiol. 2005;96(9A):65K–70K. discussion 34K–35K.
  • Charlab R, Zhang L. Pharmacogenomics: historical perspective and current status. Methods Mol Biol. 2013;1015:3–22.
  • Yip LY, Chan EC. Investigation of host-gut microbiota modulation of therapeutic outcome. Drug Metab Dispos. 2015;43(10):1619–1631.
  • Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–1273.
  • Sistigu A, Viaud S, Chaput N, et al. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011;33(4):369–383.
  • Schiavoni G, Sistigu A, Valentini M, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71(3):768–778.
  • Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004;34(2):336–344.
  • Viaud S, Flament C, Zoubir M, et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res. 2011;71(3):661–665.
  • Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–976.

•This paper provides evidence for gut microbial impacts on drug efficacy such as with cyclophosphamide.

  • Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–970.
  • Vanhoefer U, Harstrick A, Achterrath W, et al. Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol. 2001;19(5):1501–1518.
  • Stringer AM, Gibson RJ, Logan RM, et al. Faecal microflora and beta-glucuronidase expression are altered in an irinotecan-induced diarrhea model in rats. Cancer Biol Ther. 2008;7(12):1919–1925.
  • Takasuna K, Hagiwara T, Hirohashi M, et al. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 1996;56(16):3752–3757.
  • Wallace BD, Wang H, Lane KT, et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 2010;330(6005):831–835.
  • Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–239.
  • Barber MJ, Mangravite LM, Hyde CL, et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One. 2010;5(3):e9763.
  • Kaddurah-Daouk R, Baillie RA, Zhu H, et al. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One. 2011;6(10):e25482.
  • Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504–516.
  • Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA. 2009;106(10):3698–3703.
  • Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science. 2012;336(6086):1262–1267.

•This review discussed the intricate relationship between host and gut microbiota.

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