Review
The effect of gut microbiota on
1. Introduction
2. Drug metabolism by host
tissues and intestinal
microbiota
3. Role of metabolism of natural
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/14/14
products by intestinal
microbiota in their action
4. Role of metabolism of
synthetic drugs by intestinal
microbiota in their action
5. Expert opinion
For personal use only.
10.1517/17425255.2013.807798 © 2013 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607
All rights reserved: reproduction in whole or in part not permitted
drug metabolism
Mi Jeong Kang, Hyung Gyun Kim, Jin Sung Kim, Do Gyeong Oh,
Yeon Ji Um, Chae Shin Seo, Ji Won Han, Hyun Ji Cho, Ghee Hwan Kim,
Tae Cheon Jeong & Hye Gwang Jeong†
†
Chungnam National University, College of Pharmacy, Daejeon, South Korea
Introduction: Numerous drugs and toxicants must be metabolized to an active
form. Metabolic activation by host tissues, such as the liver, has been well
studied. However, drug and toxicant metabolism by the intestinal microbiota
is an unexplored, but essential, field of study in pharmacology and toxicology.
The taxonomic diversity and sheer numbers of the intestinal microbiota, and
their capacity to metabolize xenobiotics, underscore the importance of this
mode of metabolism.
Areas covered: Metabolism by the intestinal microbiota has focused on the
natural products of glycosides hydrolyzed by intestinal microbiota enzymes,
but not by host tissues. Metabolism of synthetic drugs by the intestinal micro-
biota has been less-intensively investigated. This review provides an overview
of xenobiotic metabolism by the intestinal microbiota of both natural
products and synthetic drugs.
Expert opinion: Metabolism by the intestinal microbiota might result in a dif-
ferent metabolite profile than that produced by host tissues. This could
potentially result in either activation or inactivation of the pharmacological
and/or toxicological actions of the compound in question. The contribution
of the intestinal microbiota to drug metabolism remains relatively unex-
plored. Therefore, studies of xenobiotic metabolism by the intestinal micro-
biota need to be included in new drug development as well as classical
studies of host tissue metabolism.
Keywords: drugs, gut microbiota, metabolism, natural products
Expert Opin. Drug Metab. Toxicol. (2013) 9(10):1295-1308
1. Introduction
Hepatic metabolism is classified into Phase I and Phase II reactions, based on the
hydrophilicity of the metabolites produced. Metabolism is a major clearance mech-
anism of the 200 drugs most commonly prescribed in 2002, which indicates the
importance of metabolism in drug action [1]. Phase I enzymes, such as cytochrome
P450 (CYP), contribute to the majority of xenobiotic clearance; CYP3A4,
CYP2C9, CYP2C19 and CYP2D6 have the greatest effects. Together, these
enzymes are responsible for ~ 80% of drug oxidation [2]. Through metabolism,
drugs can be either inactivated or activated. For this reason, predicting drug inter-
actions, including reaction phenotypes, is an essential part of development of new
chemical entities [3]. The major drug metabolizing enzymes in the liver involved
in Phase I and Phase II reactions have been investigated intensively. However,
drug metabolism in tissues may not encompass the entire xenobiotic metabolism
occurring in the human body due to the existence of the highly metabolically active
intestinal microbiota.
It is estimated that > 1000 species of microorganisms are contained in the human
intestine, numbering ~ 1014 microbes, which is ~ 10 times greater than the number
1295
 M. J. Kang et al.
Article highlights.
. Pharmacological and toxicological metabolism by the
intestinal microbiota is an unexplored, but essential, field
of study in pharmacology and toxicology.
. Metabolism by the intestinal microbiota can result in a
different metabolite profile than that produced by host
tissues during either activation or inactivation of drugs.
. Dozens of xenobiotics are ultimately or intermediately
metabolized by the intestinal microbiota and can be
summarized by their relationship between
pharmacological actions and gut metabolism.
. Although most examples of xenobiotic metabolism by
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the intestinal microbiota are natural products containing
glycoside linkages, the available examples of synthetic
drug metabolism underscore the importance of the
intestinal microbiota.
. Studies of xenobiotic metabolism by the intestinal
microbiota should be included in new drug
development, in addition to the classical studies of
metabolism by host tissues.
This box summarizes key points contained in the article.
of human cells in the body [4,5]. Three factors should be taken
into consideration when examining xenobiotic metabolism by
For personal use only.
the intestinal microbiota [6,7]. First, intestinal microorganisms
exhibit various xenobiotic-metabolizing capacities. Second,
individual human host varying species and numbers of intes-
tinal microbiota. Third, the intestinal microbiota is tran-
siently affected by environmental factors, such as diet and
administration of antibiotics. Thus the actions of xenobiotics,
including drugs that are affected by the intestinal microbiota,
differ to an extent among individuals. For example, we
reported recently that the toxicities toward mammalian cells
of some xenobiotics, such as arbutin, baicalin, geniposide
and butyl paraben, are modulated through their metabolism
by the human intestinal microbiota [8-11]. In addition, in our
recent review of the role of metabolism by the intestinal
microbiota in xenobiotic-induced toxicity, we presented
examples of xenobiotic toxicity that was either potentiated
or diminished by the intestinal microbiota [12].
In addition to the drug-metabolizing enzymes in host tis-
sues, the intestinal microbiota can either activate or inactivate
drugs via metabolism. The oral bioavailability and half-life of
drugs can also be influenced through metabolism by the intes-
tinal microbiota. Dozens of xenobiotics, including drugs, are
ultimately metabolized by the intestinal microbiota, and their
pharmacological actions modulated [13]. Nevertheless, the role
of the intestinal microbiota in drug action has still been
underestimated. The present review is intended to give an
overview of the importance of drug metabolism by the intes-
tinal microbiota using examples of natural products and syn-
thetic drugs. The compounds mentioned in this review were
selected, in principle, to emphasize that the intestinal metab-
olism might be critical in pharmacological actions of certain
xenobiotics, because the toxicological aspects were already
1296 Expert Opin. Drug Metab. Toxicol. (2013) 9(10)
mentioned in our previous report [12]. Pharmacological
actions requiring metabolism by intestinal microbiota have
mainly been investigated with natural products. In addition,
the studies with synthetic drugs need more thorough attention
in the near future. Therefore, we categorized the compounds
to be reviewed into natural products and synthetic drugs of
which metabolism by intestinal microbiota are essentially
required.
2. Drug metabolism by host tissues and
intestinal microbiota
Xenobiotic metabolism in the small and large intestines differs
from metabolism in host tissues. For example, the redox
potential in the intestine favors the reduction reaction due
to the low oxygen tension, reducing environment, whereas
oxidation is favored in tissues such as the liver [13]. In addi-
tion, the ability to metabolize xenobiotics by the intestinal
microbiota differs markedly among individuals due to differ-
ences in the resident microbiota [14]. The intestinal microbiota
not only catalyzes reduction, but is involved in numerous
metabolic reactions, such as dehydroxylation, acetylation,
ring opening, dealkylation and hydrolysis of glycosides, glu-
curonides and sulfates, which are either ingested orally or
excreted into the intestine through Phase I and Phase II reac-
tions in host tissues [13]. The possible consequences of intesti-
nal microbial metabolism of xenobiotics are summarized
in Table 1. Xenobiotic metabolism by the intestinal micro-
biota is predicted to change the enterohepatic circulation of
metabolites excreted from host tissues, by which the efficacy
and/or toxicity of xenobiotics that require metabolism for
their actions is modulated [13,15]. Therefore, understanding
the metabolism of xenobiotics by the intestinal microbiota
might be an additional factor controlling the biological
actions of xenobiotics. At present, intensive studies are
urgently required because only about 40 therapeutic drugs
have been investigated for their metabolism by the intestinal
microbiota [16]. In addition, the specific microbes responsible
for xenobiotic metabolism remain largely uncharacterized [16].
Xenobiotic metabolism by the intestinal microbiota has
been investigated in several ways. The simplest technique is
to use intestinal contents or faecal suspensions prepared
from animals, including humans [12,13,16]. With this approach,
the maintenance of anaerobic conditions is a critical factor for
mimicking the low oxygen tension present in vivo. However,
many studies did not maintain strict anaerobic conditions. In
addition, faecal suspensions are not stable as an enzymatic
source; therefore, only freshly isolated specimens provide
meaningful results [12]. Despite these limitations, this strategy
has provided valuable insights regarding the role of intestinal
microbial metabolism in the pharmacological and/or
toxicological actions of many xenobiotics.
In any investigation of xenobiotic metabolism by the
intestinal microbiota, identification of the metabolite(s)
produced is essential. Analytical techniques, such as liquid
 The effect of gut microbiota on drug metabolism

Table 1. Consequences of xenobiotic metabolism by intestinal microflora.

Consequences Examples Refs.

Increased toxicity: production of toxic or carcinogenic 2-Amino-3-methylimidazo[4,5-f]quinolone (IQ), arbutin, [8,10,12]

metabolites geniposide, rutin
Decreased toxicity or detoxication Baicalin, butyl paraben, ochratoxin A, zearalenone [9,11,12]
Modulation of hepatic and intestinal drug-metabolizing CYP 1A, glutathione S-transferases, epoxide hydrolases, [15,117]
enzymes sulfotransferase, N-acetyl transferase, glutathione peroxidase
Enterohepatic circulation resulting in delayed excretion Sulindac, a variety of xenobiotics excreted into bile as [13,15]
glucuronide or sulfate conjugates
Production of pharmacologically active metabolites Sulfa drugs including prontosil, many examples in this paper [12,13,15]
Species variation in metabolism and toxicity Irinotecan [16,118]
Differences in efficacy and toxicity resulting from the Irinotecan, natural products containing b-glycoside moiety
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[12,16,118]
routes of administration reviewed in this paper
Production of metabolites not formed in tissues Irinotecan, natural products containing b-glucuronide, [12,118]
sulfate and glutathione excreted into bile

chromatography associated with mass spectrometry (LC/MS),
are available for such studies and can provide information
on metabolite formation from various intestinal microbial
enzyme sources sampled under anaerobic conditions. The
role of intestinal microbial metabolism in the pharmacologi-
cal actions or toxicity of xenobiotics can also be studied
in vitro using bacterial or mammalian cell culture. The direct
effects of the parent compound and its metabolites, either
For personal use only.
intestinal bacteria, both of which require a specialized isola-
tion facility. Using such a model, the metabolites produced
by the intestinal microbiota can be identified, and the role
of metabolism by the intestinal microbiota in the biological
actions of xenobiotics is investigated [12].
The following sections give an overview of the role of
metabolism by the intestinal microbiota in xenobiotic-
induced pharmacological actions. The main part of this

commercially available or prepared by researchers based on
specific parameters, can be studied using this approach. Spe-
cific xenobiotics can also be incubated with intestinal micro-
bial enzyme sources to compare the effects of the parent
xenobiotic with metabolites. When the biological actions of
metabolites are studied in mammalian cell cultures, a steriliza-
tion procedure must be employed. To date, three types of
enzyme source have been tested: selected cultures of human
intestinal bacteria, human fecal suspensions or fecalase and a
sonicated enzyme mixture of four human intestinal bacteria
selected for their potent hydrolysis activities [8-11,17]. Since
the sonicated enzyme mixture maintains its enzymatic activity
for at least 4 months with good performance in the Ames test,
it is the recommended model for in vitro metabolic activation
by the intestinal microbiota, as the Aroclor-induced S9
fraction is recommended for use in the classical Ames test as
a host tissue metabolic activation system [17].
The ultimate model for investigating the role of meta-
bolism by the intestinal microbiota in xenobiotic activity is
in vivo. An antibiotic-pretreated model provides relatively
simple control of the cell density of the intestinal microbiota.
Antibiotics cannot eliminate all microorganisms from the
intestine, but the model is sufficient to study the role of the
intestinal microbiota in xenobiotic metabolism. In addition,
antibiotic models can be managed in a general facility for
laboratory animal maintenance. For this reason, many
studies using antibiotic-pretreated animals have been con-
ducted [12,13]. However, the antibiotics used in these models
can interact with xenobiotics, which might interfere with the
study results. The ultimate in vivo model would require
germ-free animals and gnotobiotic animals containing specific
review deals with natural products since most investigations
have been done with natural glycosides. Next, the role of
metabolism by intestinal microbiota in synthetic drugs-
induced pharmacological actions is described. Finally, our
opinion to emphasize specific investigations needed mostly
for understanding metabolism of xenobiotics by intestinal
microbiota was mentioned.
3. Role of metabolism of natural products by
intestinal microbiota in their action
Historically, extracts of natural products have been widely
used for the treatment of a variety of diseases. Ingredients iso-
lated from these extracts possess in most cases both unique
and similar pharmacological actions. The natural products
known to be metabolized by the intestinal microbiota are
listed in Table 2. The majority of these studies assessed com-
pounds containing glycosidic linkages. The first step in glyco-
side metabolism in the intestine is hydrolysis by glycosidases
produced by the intestinal microbiota. Individual studies
have focused on the identification of metabolites produced
by the intestinal microbiota, and subsequent comparative
studies assessed differences in the pharmacological potencies
of the parent compounds and their metabolites.
Barbaloin, a C-glycoside present in aloe, is metabolized to
the deglycosylated aloe-emodin anthrone in human fecal
suspensions and in both conventional and gnotobiotic rats
containing Eubacterium sp. [18]. The microbial metabolite,
aloe-emodine anthrone, exerts a cathartic effect in animals
by increasing the permeability of the colonic mucosa, whereas
barbaloin does not [19].

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 M. J. Kang et al.

Table 2. Natural products that require metabolism by intestinal microflora in their pharmacological actions.

Compounds Evidence for the role of metabolism by intestinal microflora (IM) Refs.
in pharmacological actions

Barbaloin -- Oral barbaloin showed cathartic effects in gnotobiotic rats containing Eubacterium sp. [18]
capable of transforming to aloe-emodin anthrone.
-- Aloe-emodin anthrone-induced cathartic effects were observed by increased permeability [19]
in colon mucosa.
Baicalin -- Metabolism by IM to baicalein is essential for intestinal absorption. [20-22]
-- Metabolism of baicalin to baicalein by IM reduced cytotoxicity and apoptosis. [9]
-- Baicalein and oroxylin A from baicalin by IM showed anti-pruritic and anti-inflammatory [23,24]
effects than baicalin.
-- Baicalein could be converted to baicalin after intestinal absorption.
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[25]
-- Baicalein was more cytotoxic to various cancer cells than baicalin. [26]
-- Free radical scavenging and anti-angiogenic effects of baicalein were more potent than [27,28]
baicalin.
Daidzein -- Dihydrodaidzein, equol and O-desmethylangolesin were produced by human, monkey or [29,30]
mouse intestinal bacteria.
-- Metabolites were well produced in gnotobiotic rodents containing intestinal bacteria, [31]
but not in germ-free rats.
-- The metabolite, equol, showed the most potent effects, including antitumor activity. [32,33]
Geniposide -- Eubacterium sp. from human faeces could produce genipin, whereas liver homogenates [34]
could not.
-- Cytotoxicity and apoptotic effects of genipin on several tumor cells were more potent than [10,35]
geniposide.
Genistein -- Genistein to 5-hydroxyequol or 6’-hydroxy-O-demethylangolesin by intestinal bacteria [29,36]
was well documented.
-- Although biological activity of metabolites from genistein was not studied well, genistein
For personal use only.

[37]
had more potent activity than genistin, the parent glucoside.
Ginsenoside Rb1 -- Ginsenoside Rd, F2 and compound K were produced by human fecal suspension. [38,39]
-- Metabolism to compound K is needed for inducing apoptosis in tumor cells. [39]
Ginsenoside Re -- Ginsenoside Rg1, Rg2, F1, Rh1 and protopanaxatriol were produced by human fecal [38,40]
suspension and Rh1 was most abundant among metabolites.
-- Estrogenic effects of Rh1 in MCF-7 cells were more potent than Re. [40]
Glycyrrhizin -- 18b-Glycyrrhetinic acid was mainly produced by human fecal suspension and a form [41,42]
observed in serum when glycyrrhizin was administered orally.
-- 18b-Glycyrrhetinic acid was only produced in conventional and gnotobiotic rats, [41]
but not in germ-free rats when glycyrrhizin was orally administered.
-- Hepatoprotective effects of glycyrrhizin were only seen when administered orally, [43,44]
but not intraperitoneally or in germ-free rats.
Hesperidin -- Hesperetin was mainly produced by human IM or fecal suspension. [45-47]
-- Hesperetin was observed in urine following oral hesperidin in human. [47]
-- Plasma hesperetin level was reduced in antibiotic-treated rats. [48]
-- Effects of hesperetin were more potent than hesperidin in tumor cell killing, inhibition [49,50]
of passive cutaneous anaphylaxis, and anti-inflammation.
Kakkalide -- Irisolidone was produced by human fecal suspension. [51,52]
-- Estrogenic effect of irisolidone was more potent than kakkalide. [51]
-- Protective effect of irisolidone against ethanol-induced hepatotoxicity was more [52]
potent than kakkalide.
Naringin -- Naringenin and propionic acid metabolites were produced by human fecal suspension [53,54]
and some IMs.
-- Cytotoxic effects of naringenin on several tumor cells were more potent than naringin [53,54]
-- Effects of naringin and naringenin on hepatic cholesterol, antioxidant enzymes, and [55,56]
inflammation were comparable.
Poncirin -- Poncirin was metabolized to poncirenin and ponciretin by human IM. [57]
-- Ponciretin showed lower minimum inhibitory concentration to Helicobacter pylori than [57]
poncirin.
-- Ponciretin suppressed vacuolating cytotoxin-induced apoptosis in HeLa cells than poncirin. [58]
Puerarin -- Daidzein (major metabolite), dihydrodaidzein and equol were produced by human fecal [36,59,60]
suspension and in vivo.
-- Estrogenic and anti-thrombotic effects of daidzein were more potent than puerarin. [60,61]
-- For anticancer activity, metabolism of puerarin to daidzein and to further conjugates [62]
would be required.

1298 Expert Opin. Drug Metab. Toxicol. (2013) 9(10)

 The effect of gut microbiota on drug metabolism

Table 2. Natural products that require metabolism by intestinal microflora in their pharmacological actions
(continued).

Compounds Evidence for the role of metabolism by intestinal microflora (IM) Refs.
in pharmacological actions

Rhaponticin -- Rhapontigenin was produced by human fecal suspension. [63]

-- Anti-allergic activity as measured in the inhibitory potential on b-hexosaminidase expression [63]
was only seen by rhapontigenin, but not by rhaponticin.
-- Inhibitory effects of rhapontigenin on CYP 1A1 enzyme were 500 times greater than [64]
rhaponticin.
Rutin -- > 8 metabolites including quercetin and 3,4-dihydroxyphenylacetic acid were produced by [65]
human IM.
-- Mostly pharmacological activities of quercetin, such as anti-apoptotic and antioxidant
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[66-68]
activity, were greater than rutin with some exceptions.
Sennoside A, -- Rhein anthrone was produced as a final metabolite following various steps by intestinal [69,70]
B and C bacteria.
-- Rhein anthrone was an ultimate metabolite to show the potent cathartic effects of [70]
sennoside in vivo.
Syringin -- Sinapyl alcohol was produced by human fecal suspension. [71]
-- Cytotoxic effects of sinapyl alcohol on several tumor cells were more potent than syringin. [71]
-- Sinapyl alcohol reduced acute paw edema induced by carrageenan in vivo and inhibited. [71]
LPS-induced production of NO, prostaglandin E2 and tumor necrosis factor-a in vitro than
syringin.
Tectoridin -- Tectorigenin was produced by human fecal suspension. [51]
-- Tectorigenin showed more potent estrogenic and anti-allergic activities than tectoridin. [51]
-- Tectorigenin showed more potent suppression of COX-2 protein expression and free radical [72,73]
scavenging activity than tectoridin.
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Baicalin, a 7-glucuronide of baicalein present in scutellar-
iae radix, is an interesting natural product. Intestinal micro-
organisms that produce b-glucuronidase can hydrolyze it to
baicalein, an aglycone form that is absorbed by the
intestine [20-22]. Upon adsorption, baicalein is reglucuroni-
dated by UDP-glucuronosyltransferase in tissues to baicalin
and baicalein-6-glucuronide [21,22]. Reports of the pharma-
cological activities of baicalin and baicalein in vivo indicate
that baicalein might exert several types of activity [23-28].
Several other metabolites, including oroxylin A, have also
been identified to possess pharmacological activities [23,24].
The metabolic pathway suggested that the initial metabo-
lism to baicalein by the intestinal microbiota determines
the bioavailability and pharmacological action of baicalin
in the body.
Together with genistein, daidzein is a core isoflavone com-
pound present in soy-containing foods. Daidzin and puerarin
in soy-containing foods, as well as Puerariae radix, are com-
monly deglycosylated to daidzein or the biologically active
dihydrodaidzein, O-desmethylangolesin and equol by the
intestinal microbiota [29-31]. The pharmacological effects of
equol are more potent than daidzein in many experimental
cancer models, including tumor cell cytotoxicity, inhibition
of neoplastic transformation in mouse epidermal cells and
suppression of dimethylbenzanthracene-induced mammary
carcinoma in rats [32,33]. Only one-third of humans possess a
microbiota capable of transforming daidzein into equol, indi-
cating that intestinal metabolism of daidzein could underlie
the variation in daidzein activity among individuals [30].
Geniposide, one of the major iridoid glycosides in gardenia
fruits, is hydrolyzed to its aglycone genipin by Eubacterium sp.
isolated from human feces [34]. Studies of the cytotoxicity and
pro-apoptotic activities on hepatoma cells indicated that the
effects of genipin are more potent than those of geniposide [35].
Because metabolism of geniposide to genipin in liver homog-
enate fractions is negligible, metabolism to genipin by the
intestinal microbiota is likely critical for the pharmacological
action of geniposide [34]. Our recent studies also suggested
that metabolism of geniposide to genipin by human fecal
suspensions might be necessary for the pro-apoptotic action
of geniposide in HepG2 cells [10].
Genistein, the most abundant isoflavone in soybeans,
contains one more hydroxyl group at the 5-position of
daidzein. Its metabolism by intestinal bacteria is so similar
to daidzein that genistein can be metabolized to dihydro-
genistein, hydroxy-O-desmethylangolesin and 5-hydroxy
equol [29,36]. Most pharmacological studies have been per-
formed using genistein and genistin, the glycosidic form,
but not the metabolites of genistein, likely due to their
lack of biological activities. Compared with genistin, the
pro-apoptotic effects of genistein were more potent in
human ovarian cancer cells, as measured by cell cycle arrest
and caspase-3 activity [37].
Ginsenoside Rb1, a protopanaxadiol in ginseng, can
be metabolized to Rd, F2, Rg3 and compound K by the
intestinal microbiota [38,39]. A collective metabolic pathway
with specific microorganisms has been well described [32].
The final metabolite, compound K, showed potent

Expert Opin. Drug Metab. Toxicol. (2013) 9(10) 1299

 M. J. Kang et al.
pro-apoptotic effects in tumor cells via modulation of
several apoptosis-related proteins [39].
Ginsenoside Re, a protopanaxatriol in ginseng, can be
metabolized to ginsenosides Rg1, Rg2, F1 and Rh1 by the
human intestinal microbiota [38,40]. The metabolic pathway,
which is mediated by specific microorganisms, has been well
described [38]. Among the metabolites, ginsenoside Rh1
exerted stronger estrogenic effects in MCF-7 cells than did
ginsenoside Re [40].
Glycyrrhizin, a diglucuronide from Glycyrrhizae herba, is
metabolized to 18b-glycyrrhetinic acid monoglucuronide and
18b-glycyrrhetinic acid by human fecal suspensions, specific
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microorganisms (such as Eubacterium sp. and Bacteroides sp.)
or in vivo [41,42]. Human liver b-glucuronidase does not
produce 18b-glycyrrhetinic acid, but does produce 18b-
glycyrrhetinic acid monoglucuronide [42]. Metabolism to
18b-glycyrrhetinic acid is necessary for the pharmacological
actions of glycyrrhizin. Protective effects of glycyrrhizin against
carbon tetrachloride-induced hepatotoxicity have been identi-
fied only in gnotobiotic rats, not in germ-free rats [43]. Like-
wise, hepatoprotection by glycyrrhizin is seen only when
administered orally, not by intraperitoneal injection [44]. These
results demonstrate the critical importance of metabolism to
18b-glycyrrhetinic acid in the intestine prior to absorption.
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Hesperidin (hesperetin-7-O-rutinoside), present in citrus
fruits, is primarily metabolized to its aglycone, hesperetin,
by the human intestinal microbiota [45-47]. Hesperetin has
been detected in urine following oral administration to
humans; use of oral antibiotics in rats significantly reduces
plasma hesperetin levels. Therefore, hesperetin production
by the intestinal microbiota is essential for absorption [47,48].
Hesperetin exhibits greater potency than hesperidin in terms
of several effects, including tumor cell killing [49,50].
Kakkalide, an isoflavone from puerariae flos, is metabo-
lized to kakkalidone, a monoglucosidic form, and irisoli-
done, the aglycone, by human fecal suspensions [51,52]. The
estrogenic effects of irisolidone in MCF-7 cells were greater
than those of kakkalide, as measured by means of the expres-
sion of estrogen-responsive c-fos and pS2 mRNAs [51]. Pro-
tection by kakkalide against ethanol-induced toxicity was
identified upon oral administration, and only weakly when
administered intraperitoneally [52].
Naringin, a flavone from grape fruits, can be deglycosylated
to naringenin and, subsequently, to its propionic acid metab-
olites and phloroglucinol by human fecal suspensions [53,54].
Structurally similar compounds, such as quercetin, apigenin
and luteolin, undergo similar metabolism by the intestinal
microbiota [53,54]. Naringenin and its metabolites, such as
3-(4-hydroxyphenyl) propionic acid, inhibit hydroxymethyl
glutaryl-CoA (HMG-CoA) reductase and induce antioxidant
enzymes, such as hepatic superoxide dismutase and gluta-
thione peroxidase, which leads to reduction of hepatic
cholesterol and lipid peroxidation [55,56].
Poncirin, a glycoside of flavone isolated from Poncirus sp.,
can be metabolized to ponciretin monoglucoside, ponciretin,
1300 Expert Opin. Drug Metab. Toxicol. (2013) 9(10)
an aglycone of poncirin, naringin, a demethylated form of
poncirin, and naringenin by the human intestinal micro-
biota [57]. Among these compounds, ponciretin inhibits the
growth of Helicobacter pylori and vacuolating cytotoxin-
induced apoptosis most effectively by inhibiting procaspase-
3 activation [57,58]. The activities of poncirin, naringin, narin-
genin, hesperidin and hesperetin were compared with that of
ponciretin [58].
As mentioned above, puerarin, a C-glycoside of daidzein
that was isolated originally from puerariae radix, is metabo-
lized primarily to daidzein, dihydrodaidzein and equol
in vivo and by human fecal suspensions [36,59,60]. The estro-
genic, anti-thrombotic and anti-allergic potencies of daidzein
are greater than those of puerarin [60,61]. Interestingly, daid-
zein sulfate and glucuronide significantly increase the expres-
sion of caspase-9 and bax in breast cancer cells, indicating
that Phase II metabolism of daidzein is necessary for its
anticancer activity [62].
Rhaponticin, a stilbene glucoside from Rheum undulatum,
can be metabolized to rhapontigenin, the aglycone, by human
fecal suspensions [63], and the pharmacological effects of rha-
pontigenin are greater than those of rhaponticin. For example,
inhibition of b-hexosaminidase expression occurs only with
rhapontigenin in RBL 2H3 cells, and rhapontigenin exhibited
highly potent anti-coagulating effects in the collagen-induced
platelet aggregation model [63]. In addition, the inhibitory
effect of rhapontigenin on human CYP1A1 enzyme is 500
times greater than that of rhaponticin [64].
Metabolism of rutin, a flavonoid glycoside found in many
citrus fruits, by the human intestinal microbiota results in sev-
eral metabolites, including quercetin-3-O-glucoside, querce-
tin, the aglycone and 3,4-dihydroxyphenylacetic acid [65].
Although, intraperitoneal rutin has anti-inflammatory
activity, quercetin also exhibits anti-apoptotic and anti-
oxidant effects in vitro, as well as therapeutic effects on
hyperuricacidemia in mice [66-68].
Metabolism of sennosides A, B and C, anthraquinone gly-
cosides used as a laxative, results in various products, includ-
ing the final metabolite rhein anthrone [69,70]. In vivo studies
indicate that rhein anthrone might be ultimately responsible
for the potent cathartic effects of sennosides [70].
Syringin, a glucoside present in many plants, such as Acan-
thopanax sp. and bark of lilac, can be metabolized to sinapyl
alcohol by human fecal suspensions [71]. In addition to cyto-
toxic effects on several tumor cell types, sinapyl alcohol exhib-
its greater effects than syringin on suppression of acute paw
edema induced by carrageenan in vivo and inhibition of
LPS-induced production of NO, prostaglandin E2 and
TNF-a in vitro [71].
Tectoridin, an isoflavone isolated from the flower of Pueraria
thunbergiana, can be metabolized to its aglycone, tectorigenin,
by human fecal suspensions [51]. In addition to its estrogenic
and anti-allergic activities, tectoridin requires metabolism to
tectorigenin for potent suppression of COX-2 expression, as
well as for its free radical scavenging activity [51,72,73].

4. Role of metabolism of synthetic drugs by
intestinal microbiota in their action
The roles of the intestinal microbiota in metabolism and
activities of synthetic drugs are summarized in Table 3.
Although the examples are relatively limited, the consequen-
ces of metabolism by the intestinal microbiota are critical to
the activities of some drugs.
The effects of the intestinal microbiota on acetaminophen
metabolism have been investigated, even though the struc-
tures of metabolites have not been characterized. Following
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/14/14
antibiotic treatment of rats, the levels of acetaminophen gluta-
thione conjugates in the blood were much higher than those
in untreated rats, indicating a possible role for the intestinal
microbiota [74]. In addition, a role for the intestinal micro-
biota in metabolism of acetaminophen-3-cysteine, which
may be excreted into bile as a glutathione conjugate, has
been suggested [75,76].
The reduction of digoxin to dihydrodigoxin by the intesti-
nal microbiota may be involved in its pharmacological inhibi-
tion of the Na+/K+-ATPase. In ~ 10% of patients taking
digoxin, dihydrodigoxin was detected in urine, the level of
which was significantly reduced by antibiotic pre-treat-
ment [77]. Later, digoxin-metabolizing Eggerthella sp. was
For personal use only.
identified in the intestine, and was shown to inactivate the
cardio-activity of digoxin [78]. Therefore, inter-individual
variation might be due to digoxin-metabolizing enzymes of
the intestinal microbiota, of which was investigated in
volunteers living in southern India and the United States [79].
The serial metabolism of L-dopa to m-hydroxyphenylacetic
acid by the intestinal microbiota was characterized in a com-
parative study using cecal contents prepared from conven-
tional and germ-free rats. Due to the lack of metabolism to
m-tyrosine from L-dopa, germ-free rats could not produce
the final metabolite, m-hydroxyphenylacetic acid [80]. The
role of the intestinal microbiota in L-dopa metabolism is sup-
ported by the significant reduction in the urinary m-hydroxy-
phenylacetic acid level upon antibiotic pre-treatment in
patients taking L-dopa for Parkinsonism [81,82].
Flucytosine requires metabolism to 5-flurouracil by the
intestinal microbiota for its antimycotic and antitumorigenic
activities [83,84]. Pre-treatment of cancer patients with antibi-
otics or intravenous injection of flucytosine abolishes produc-
tion of active 5-fluorouracil, which supports the role of the
intestinal microbiota in the action of flucytosine [84,85].
The mode of drug activity upon intravenous administration
can also be modulated by the intestinal microbiota. Irinotecan,
a semi-synthetic anticancer agent with a camptothecin moiety
that is injected intravenously, is metabolized to active SN-38
by carboxyesterases in tissues and blood [16]. When the glucu-
ronide conjugate of SN-38 produced in tissues is subsequently
excreted into the intestine, it is hydrolyzed by the intestinal
microbiota to SN-38, resulting in severe diarrhea and weight
loss [16,86-88]. Therefore, treatment with oral antibiotics to
block the side effects of irinotecan is recommended [87,88].
Expert Opin. Drug Metab. Toxicol. (2013) 9(10)
The effect of gut microbiota on drug metabolism
When loperamide oxide is reduced to loperamide by the
intestinal microbiota, an anti-diarrheal effect is evident [89].
The cecal contents of animals, including humans, effectively
reduce loperamide oxide, although the reductase activity was
negligible in cecal contents from germ-free rats [89].
Metronidazole can be metabolized to N-(2-hydroxyethyl)
oxamic acid and acetamide by the cecal contents of conven-
tional animals, but not germ-free animals, indicating the
involvement of the intestinal microbiota in the fate of metro-
nidazole [90]. In fact, some intestinal bacteria, including
Enterococcus sp., could produce nitro-reductase enzymes [91].
The role of the intestinal microbiota in metabolism of
H2-receptor antagonists has been investigated. Among them,
nizatidine, but not cimetidine and famotidine, are degraded
by human fecal suspensions, possibly to N-reduced
metabolites [92].
Olsalazine, an agent used for treatment of inflammatory
bowel disease that has two 5-aminosalicylic acids moieties
linked to an azo group, can be reduced to 5-aminosalicylic
acid, the active metabolite, by the intestinal microbiota [93,94].
Several in vivo studies indicate that decreased plasma levels of
olsalazine are closely related to the production of 5-aminosa-
licylic acid and its N-acetylated form [95,96]. In addition, the
colonic microbiota can reduce similar derivatives, such as
sulfasalazine and balsalazide, to 5-aminosalicylic acid [93,94].
Simvastatin, an HMG-CoA reductase inhibitor used for
treatment of hyperlipidemia, can be metabolized to several
metabolites, including 3-hydroxybutanoic acid and cyclohex-
anecarboxylic acid, by the intestinal microbiota [97]. This sug-
gests that the bioavailability of simvastatin can be modulated
by the individual state of intestinal microbiota.
Sodium picosulfate can be hydrolyzed to bis-(p-hydroxy-
phenyl)-pyridyl-2-methane (BHPM) by the intestinal micro-
biota, which mediates its laxative action [98,99]. BHPM is
also produced by the sulfotransferase, but not the sulfatase,
of Eubacterium sp. isolated from the human intestine [98].
The anti-viral agent sorivudine can be metabolized by
the intestinal microbiota, but not by host tissues, such as the
liver, kidney and intestine, to 5-(E)-(2-bromovinyl) uracil
(BVU) [100]. Several Bacteroides sp. metabolize sorivudine to
BVU [100]. Toxicological interaction of sorivudine with
5-fluorouracil has been described elsewhere [101,102]. BVU is
a potent inactivator of dihydropyrimidine dehydrogenase,
which is responsible for the metabolism of 5-fluorouracil, an
anticancer agent, to nontoxic metabolites. Therefore, inhibi-
tion of this enzyme could cause a significant elevation in
plasma 5-fluorouracil levels, which may account for the
18 reported deaths that occurred when these two drugs were
co-administered [101,102]. In vivo studies using antibiotic-
treated rats demonstrated that the production of BVU was
directly related to the intestinal microbiota [100].
Sulfinpyrazone, a uricosuric agent used for treatment of
gout, contains sulfoxide that is reduced to sulfide by the intes-
tinal microbiota; however, no such activity is evident in germ-
free or antibiotic-treated rats [103]. In humans, the sulfide form
1301
 M. J. Kang et al.

Table 3. Synthetic drugs that require metabolism by intestinal microflora in their pharmacological actions.

Compounds Evidence for the role of metabolism by intestinal microflora (IM) Refs.
in pharmacological actions

Acetaminophen -- Glutathione conjugates are produced more in conventional rats than in [74]
antibiotics-treated rats.
-- IM plays a role in C-S cleavage of acetaminophen-3-cysteine in vivo. [75,76]
Digoxin -- Dihydrodigoxin could be produced by intestinal Eubacterium sp. [77]
-- Metabolism of digoxin to dihydrodigoxin by IM causes a decrease in cardio-activity to [78]
inhibit Na+/K+-ATPase and/or toxicity.
-- Reduction to dihydrodigoxin differs from person to person by the activity of [79]
anaerobic gut flora.
-- L-Dopa could be serially metabolized to m-tyrosine, m-tyramine, and m-hydroxyphenylacetic
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/14/14

L-Dopa [80]
acid only in conventional rats, but not in germ-free rats due to the lack of metabolism
of L-dopa to m-tyrosine.
-- Production of m-hydroxyphenylacetic acid was significantly reduced during L-dopa treatment [81,82]
for Parkinsonism when neomycin was co-treated.
Flucytosine -- 5-Fluorouracil could be produced by human IM, by which flucytosine gets the [83,84]
(5-fluorocytosine) anti-fungal antitumorigenic activity.
-- Production of 5-fluorouracil was significantly reduced not only by pre-treatment with [84,85]
anti-microbial agents, but by intravenous injection with flucytosine.
Irinotecan -- SN-38, an active form of irinotecan, was glucuronidated in host and excreted into bile. IM [16,86-88]
could de-glucuronidated SN-38-glucuronide to SN-38 in gut.
-- SN-38-glucuronide to SN-38 in gut induced severe diarrhea, which could be diminished by [87,88]
treatment with antibiotics.
Loperamide oxide -- Reduction to loperamide, an active form, was conducted by IM from rodents, dogs and [89]
humans only in anaerobic conditions.
-- Cecum contents from germ-free rats could not produce loperamide.
For personal use only.

[89]
Metronidazole -- N-(2-hydroxyethyl) oxamic acid and acetamide were produced in cecal contents of [90]
conventional animals, but not in germ-free animals.
-- Nitroreduction of metronidazole to active form by nitroreductase-producing intestinal [91]
bacteria were identified.
Nizatidine -- H-2 receptor antagonist, nizatidine, could be degraded by human fecal suspension, whereas [92]
cimetidine and famotidine were not.
Olsalazine -- Two 5-aminosalicylic acids were produced by IM in colon. [93,94]
-- Decreased plasma level of olsalazine was closely related with the production of [95,96]
5-aminosalicylic acid, an active form for anti-inflammation, and its N-acetylated from.
-- Similarly, azo-containing drugs including sulfasalazine could be cleaved to 5-aminosalicylic [93,94]
acid by colonic IM.
Simvastatin -- A network of simvastatin metabolism in human fecal suspension model was proposed [97]
showing the final products of 3-hydroxybutanoic acid and cyclohexanecarboxylic acid.
Sodium -- Bis-(p-Hydroxyphenyl)-pyridyl-2-methane (BHPM) was formed by sulfotransferase from IM. [98,99]
picosulfate BHPM was also produced from bisacodyl, diacetylated BHPM, by IM.
-- Production of BHPM by IM was required to act as laxatives. [99]
Sorivudine -- 5-(E)-(2-bromovinyl) uracil (BVU) could only be produced by IM, but not by host tissues, [100]
such as liver, kidney and intestine.
-- BVU inactivated dihydropyrimidine dehydrogenase, by which the detoxication of 5-fluorourail [101,102]
was blocked to cause 18 deaths.
Sulfinpyrazone -- Sulfide form was observed in blood when the IM was present: germ-free or [103]
antibiotic-treated rats could not form sulfide.
-- Sulfide was not observed in humans when the hind gut was removed or when [104]
antibiotic was administered.
-- Sulfide form was more potent than sulfinpyrazone, a sulfoxide form, in inhibiting [105,106]
platelet aggregation and cyclooxygenase activity.
Sulindac -- Reduction to sulfide, an active form, was conducted by IM from rabbits and humans [107]
in anaerobic conditions.
-- Total AUC of plasma sulfide metabolite was significantly reduced in patients with surgical [108]
ileostomy.
-- Sulfide metabolite was more potent than sulindac in not only inhibiting [109]
carrageenan-induced paw edema in rats but inhibiting uric acid-induced knee-joint
inflammation in dogs.

1302 Expert Opin. Drug Metab. Toxicol. (2013) 9(10)


is not detected in blood when the large intestine has been
removed or upon antibiotic administration [104]. The sulfide
form is more potent than the parent sulfoxide form in terms
of inhibiting platelet aggregation and cyclooxygenase
activity [105,106].
Sulindac, a non-steroidal anti-inflammatory drug, also con-
tains sulfoxide, which can be reduced to sulfide by the intesti-
nal microbiota, but not after antibiotic treatment [107]. When
the oral pharmacokinetics of sulindac were studied in patients
who had undergone surgical ileostomy, the sulfide form was
detected in only trace amounts in plasma, indicating a critical
role of the intestinal microbiota [108]. As in the case of sulfin-
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/14/14
pyrazone, the pharmacological effects of the sulfide form were
more potent than those of sulindac, the sulfoxide form, in
terms of inhibiting carrageenan-induced paw edema in rats
and uric acid-induced knee-joint inflammation in dogs [109].
5. Expert opinion
There is an urgent need to routinely evaluate the metabolism
of xenobiotics by the intestinal microbiota during drug
development.
Metabolism of xenobiotics by the intestinal microbiota
modulates their pharmacological actions and toxicities. The
For personal use only.
consequences of xenobiotic metabolism by the intestinal
microbiota are diverse and, sometimes, very critical. Some of
the examples studied to date, but not mentioned in tables,
would be updated in several online resources [110-112]. Mean-
while, many more examples will likely be reported in the
near future. As the database is accumulated, it becomes
more evident that the evaluation of metabolism by the intes-
tinal microbiota should be a routine component of drug
development. For accelerate this, the following approaches
need to be undertaken.
First, identification of members of the intestinal microbiota
that have xenobiotic-metabolizing activities is eventually
required. However, the information available at present is
very limited. Among numerous intestinal microorganisms,
known members of the intestinal microbiota capable of
metabolizing xenobiotics are only of the genera Bacteroides,
Bifidobacterium, Lactobacillus, Enterococcus, Clostridium,
Escherichia and Eubacterium [16]. At the present time, there-
fore, the systems approaches to identify individual differential
profiles of microbial community in intestine would be more
feasible to investigate the drug-microbiome interactions by
using the metagenomic analysis [15]. Although, the current
metagenomic approaches may not be able to thoroughly
explain individual drug-metabolizing phenotypes, integration
of additional approaches, such as proteomics and metabolo-
mics, would compensate its weakness. This approach would
provide an insight into possible consequences of drug actions
in person to person bases.
Secondly, an orchestration of related areas is required for
unveiling the complex interactions between drugs and
gut-associated microbes. The ultimate goal in this field is
Expert Opin. Drug Metab. Toxicol. (2013) 9(10)
The effect of gut microbiota on drug metabolism
the personalized drug therapy by understanding not only the
metabolism in host tissues but the metabolism by intestinal
microbiota [113]. In this regard, the study of drug metabolism
by intestinal microbiota is still at the beginning of its first
step, when compared to the metabolism studies in host tis-
sues. Therefore, most parts in investigating microbial drug
metabolism need a great attention by related areas. For exam-
ples, the development of tools for culturing and/or identifying
metabolites produced by either individual or populational
microorganisms would further improve the current knowl-
edge on the role of intestinal microbiota in drug metabolism.
With metagenomic approaches, the culture techniques would
be developed further, because the culturable microorganisms
currently available are very limited. The culture of individual
or populational microbiota would be useful in drug metabo-
lism studies. The analytical tools seem to be additional area
to be developed. Before the advent of LC/MS, most microbial
metabolism studies assessed the disappearance of substrates,
rather than the formation of products. Recent LC/MS techni-
ques that enable characterization of product ion fragmenta-
tion patterns made metabolite identification possible, at least
in part. However, to determine the structures of metabolites,
tools such as high-resolution NMR must be combined with
existing methods. Characterizing the individual reactions
mediated by the intestinal microbiota is also necessary for
construction of databases similar to those that exist for phar-
macogenetics and drug-drug interactions in host tissues. The
accumulation of database is desperately required due to the
limited information on drug metabolism by intestinal micro-
biota. For the start, the identification of biochemical pathways
based on the sequencing for functional modules, such as
genes, pathways and networks of pathways, would be useful
than identification of individual species at the present
time [15]. In this regard, a recent literature on the combination
of flow cytometry, 16S rRNA gene sequencing and meta-
transcrptomics to demonstrate a set of actively working
microorganisms in gut is of interest [114].
Thirdly, animal models or its alternative models should be
developed further to investigate the possible contribution of
microbiota variation in individuals and inter-individual differ-
ences in drug response and toxicity with a particular emphasis
on the metabolism of xenobiotics. As indicated above, drug
responses are modulated by the intestinal microbiota. Because
the intestinal microbiota exhibits variation among individuals,
drug activity and/or toxicity will also vary individually. Devel-
opment of personalized medications will require investigation
of the role of the microbiota in inter-individual variation in
drug actions, as well as the inter-individual genetic polymor-
phisms in host drug-metabolizing enzymes. Germ-free and
human microbiota-reconstituted gnotobiotic animal models
will be useful for investigations of variations in intestinal micro-
bial metabolism of drugs. Although maintenance of these ani-
mal models is difficult, many studies have been performed so
far (Tables 2 and 3). Antibiotic-treated models are also benefi-
cial since they mimic the pseudo-germ-free state. In addition,
1303
 M. J. Kang et al.

factors affecting the intestinal microbiota, such as diet and
disease, should be investigated.
Fourth, the drug metabolism network that includes both
hepatic enzymes and the intestinal microbiota needs to be
explored. As indicated in Table 1, the intestinal microbiota
can affect host drug metabolism either directly or indirectly.
In addition, metabolites produced by the intestinal micro-
biota can be further metabolized by host tissues and vice versa,
making for a complex metabolic pathway for each drug.
Therefore, understanding the drug metabolism network that
comprises host, principally hepatic, enzymes and the intestinal
microbiota is essential. As this information accumulates, con-
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/14/14
[8-12,17]. Using some xenobiotics, the models tried were effec-
tive, but the additional validation steps are also required.
Comparisons of xenobiotic metabolism in conventional ani-
mals with that in germ-free or gnotobiotic animals are useful
for in vivo investigations. Meanwhile, difficulties in maintain-
ing such animal models limit the generalized use in the early
stage of drug development. In addition, the lack of standard-
ized protocols for evaluation of metabolism by the intestinal
microbiota makes prediction of in vivo effectiveness difficult.
Standardized guidelines for new drug development from a
governing authority will result in availability of more effective
and reliable information on drug candidates under develop-

struction of a predictive model simulating drug response will
be possible. Understanding the role of drug transporters
would further support the predictive model. A preliminary
analysis of this type has been reported [115,116]. Clinical studies
aiming to predict the effects of personalized medication will
be possible when the variables that affect drug responses
have been characterized sufficiently.
Finally, guidelines for investigation of metabolism by the
intestinal microbiota should be prepared as an integral part
of new drug development. In the process, development of
alternative methods to study the possible role of microbial
metabolism in drug actions is required to reduce the number
For personal use only.
ment. In vitro methods mentioned above [8-12,17] would be
the candidates for first choice of method standardization. To
do so, international validation studies of in vitro testing meth-
ods, at least, for the early stage of drug development are
urgently required for better understanding the fates of drugs
in body.
Declaration of interest
The authors were supported by the grants from National
Research Foundation of Korea (2010-0026220) and from

of animals used. In this regard, cultures of intestinal micro- Yeungnam University (211-A-345-014 for MJ Kang). The
biota, suspensions of feces or intestinal contents and combina- authors also declare that their article had their language
tions of selected intestinal microorganisms that display checked and edited by the scientific editing company
xenobiotic-metabolizing activities have been studied in vitro Textcheck.

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Affiliation
Mi Jeong Kang1, Hyung Gyun Kim2,
Jin Sung Kim1, Do Gyeong Oh1, Yeon Ji Um1,
Chae Shin Seo1, Ji Won Han1, Hyun Ji Cho1,
Ghee Hwan Kim1, Tae Cheon Jeong*3 PhD &
Hye Gwang Jeong†4 PhD
*,†Authors for correspondence
1
Yeungnam University,
College of Pharmacy, Gyeongsan,
712-749, South Korea
2
Chungnam National University,
College of Pharmacy, Daejeon,
305-764, South Korea

pharmacomicrobiomics. et al. Impact of gut microbiota on 3

Curr Pharmacogenomics Person Med
2010;8:182-93
.. In this paper, a new word
‘pharmacomicrobiomics’ were used to
refer the studies how microbiome
compositional and functional
variations affect drug action, fate,
and toxicity.
114. Maurice CF, Haiser HJ, Turnbaugh PJ.
Xenobiotics shape the physiology and
For personal use only.
Yeungnam University, College of Pharmacy,
intestinal and hepatic levels of Gyeongsan, 712-749, South Korea
phase 2 xenobiotic-metabolizing enzymes Tel: +82 53 810 2819;
in the rat. Drug Metabol Dispos Fax: +82 53 810 4654;
2009;37:1179-86 E-mail: taecheon@yumail.ac.kr
4
118. Takasuna K, Hagiwara T, Hirohashi M, Professor,
et al. Involvement of beta-glucuronidase Chungnam National University,
in intestinal microflora in the intestinal College of Pharmacy, Daejeon,
toxicity of the antitumor camptothecin 305-764, South Korea
derivative irinotecan hydrochloride. Tel: +82 42 821 5936;
Cancer Res 1996;56:3752-7 Fax: +82 42 825 4946;
E-mail: hgjeong@cnu.ac.kr

1308 Expert Opin. Drug Metab. Toxicol. (2013) 9(10)