Herb Drug Interactions

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Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction

Irma Meijerman, Jos H. Beijnen and Jan H.M. Schellens
Oncologist 2006;11;742-752
DOI: 10.1634/theoncologist.11-7-742
Clinical P harmacology
HerbDrug Interactions in Oncology:
Focus on Mechanisms of Induction
Irma Meijerman,a Jos H. Beijnen,a,b Jan H.M. Schellensa,c
a
Key Words. Herbdrug interactions Chemotherapeutics Induction PXR VDR CAR
Learning Objectives
After completing this course, the reader will be able to:
1. Describe the possible pharmacokinetic interactions between complementary alternative medicines and oncolytic
drugs and the clinical consequences thereof.
2. Define the role of the nuclear receptors PXR, CAR, and VDR in herbdrug interactions.
3. Discuss methods to measure induction of drug-metabolizing enzymes and transporters.
CME
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com
Abstract
An increasing number of cancer patients are using complementary and alternative medicines (CAM) in combination with their conventional chemotherapeutic treatment. Considering the narrow therapeutic window of
oncolytic drugs, this CAM use increases the risk of clinically relevant herbanticancer drug interactions. Such
a relevant interaction is that of St. Johns wort with the
anticancer drugs irinotecan and imatinib. It is, however,
estimated that CAManticancer drug interactions are
responsible for substantially more unexpected toxicities
of chemotherapeutic drugs and possible undertreatment
seen in cancer patients.
Induction of drug-metabolizing enzymes and
ATP-binding cassette drug transporters can be one
of the mechanisms behind CAManticancer drug
interactions. Induction will often lead to therapeutic
failure because of lower plasma levels of the anticancer

drugs, and will easily go unrecognized in cancer treatment, where therapeutic failure is common.
Recently identified nuclear receptors, such as the
pregnane X receptor, the constitutive androstane receptor, and the vitamin D-binding receptor, play an important role in the induction of metabolizing enzymes and
drug transporters. This knowledge has already been an
aid in the identification of some CAM probably capable
of causing interactions with anticancer drugs: kavakava, vitamin E, quercetin, ginseng, garlic, -carotene,
and echinacea. Evidently, more research is necessary
to prevent therapeutic failure and toxicity in cancer
patients and to establish guidelines for CAM use. The
Oncologist 2006;11:742752
Correspondence: Irma Meijerman, Ph.D.,Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University Sorbonnelaan 16, PO Box 80082, 3508 TB Utrecht, The Netherlands. Telephone: 31-30-2537590; Fax: 31-30-2535180;
e-mail address: i.meijerman@pharm.uu.nl Received January 19, 2006; accepted for publication May 10, 2006. AlphaMed Press 10837159/2006/$20.00/0
The Oncologist 2006;11:742752 www.TheOncologist.com
Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University,

Utrecht, The Netherlands; bDepartment of Pharmacy & Pharmacology, Slotervaart Hospital,
Amsterdam, The Netherlands; cDepartment of Medical Oncology & Experimental Therapy,
Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
Meijerman, Beijnen, Schellens
Introduction
Clinically Relevant CAMAnticancer

Drug Interactions
One of the best known examples of a clinically significant
effect of CAM on the PK of chemotherapeutic drugs is the
herbal product St. Johns wort (SJW). SJW is very popular
among cancer patients because of its supposed activity in
mild to moderate forms of depression [4]. In cancer patients
using SJW in combination with irinotecan, the plasma levels of SN-38, the active metabolite of irinotecan, were 42%
lower [4]. The same effect was observed in rats, in which
long-term (14 days) exposure to SJW resulted in a significantly lower maximum observed concentration (C max)
of both irinotecan and SN-38 [5]. In cancer patients, the
degree of myelosuppression was substantially worse in the
absence of SJW [4]. Similarly, in the rat, gastrointestinal
and hematological toxicities after irinotecan injection were
alleviated in the presence of SJW [5]. Because of the extensive reduction in the plasma levels of SN-38, patients should
be advised to refrain from SJW use to prevent undertreatment (Fig. 1) [4]. The same advice could be given to patients
that are going to be treated with the protein-tyrosine kinase
www.TheOncologist.com
inhibitor imatinib. Healthy subjects taking imatinib combined with SJW showed a 43% greater imatinib clearance,
with up to 32% lower mean area under the concentration
time curve (AUC) and significantly lower Cmax and half-life
(t1/2). Although this may appear as a modest effect, it could
result in plasma concentrations of imatinib below the minimum effective concentration after taking the standard 400mg dose. In the case of imatinib, however, one remark has
to be made. The main metabolite formed after metabolism
of imatinib, an N-desmethylated piperazine derivative, has
been shown to have in vitro antitumor activity comparable
with that of imatinib [6, 7]. After SJW intake, the Cmax of
this metabolite was slightly greater, although the AUC from
072 hours was not different. The real clinical effect of the
lower imatinib plasma levels after SJW intake is therefore
unclear and has to be further investigated.
Based on in vitro data obtained in human hepatocyte cultures, a greater docetaxel metabolism can also be
expected in patients using SJW chronically [8].
Another example of the effect of CAM on the PK
of anticancer drugs is grapefruit juice. Grapefruit juice
intake resulted in a 26.2% lower AUC of etoposide after
oral intake. The median absolute bioavailabilities with and
without pretreatment with grapefruit juice were 52.4% and
73.2%, respectively [9].
Although to our knowledge no other clinically relevant
interactions of CAM with the PK of chemotherapeutic
drugs in patients have been reported so far, these examples
are convincing enough to assume that CAManticancer
drug interactions can be responsible for significantly more
of the large interindividual variations in the response to chemotherapeutic treatment seen in the clinic. This assumption is supported by several in vitro and in vivo studies, and
by clinical studies with other drugs, that show that some
CAMs probably have the capacity to influence plasma levels of chemotherapeutic drugs [1014].
Mechanisms of CAMAnticancer Drug

Interactions
CAManticancer drug interactions can occur at the pharmaceutical, pharmacodynamic, or PK level [15]. Interactions at the PK level are the most likely interactions to
occur and involve changes in absorption, distribution,
metabolism, or excretion of the chemotherapeutic drug.
Almost all PK interactions at the level of metabolism of
chemotherapeutic drugs involve cytochrome P450 (CYP)
metabolizing enzymes or phase II enzymes, especially
uridine diphosphoglucuronosyl transferase (UGT). Of the
CYP enzymes, CYP3A4 is the most important enzyme in
the metabolism of anticancer drugs (Table 1). In addition,
many anticancer drugs are substrates for the ATP-binding
The use of complementary and alternative medicines

(CAM) by cancer patients in the Western world has grown
rapidly. Importantly, although many cancer patients are
using CAM in combination with their conventional therapy,
more than 72% of them do not inform their treating physician about CAM use [1].
With the use of CAM in combination with conventional
chemotherapeutics, there is an increasing risk for unwanted
interactions, especially because of the narrow therapeutic
index of most oncolytic drugs. Although, as a result of a lack
of investigations, reports about clinically relevant pharmacokinetic (PK) interactions of CAM with chemotherapeutic
drugs are scarce, it is expected that CAManticancer drug
interactions contribute significantly to the interindividual
variations in PK and clinical problems of unexpected toxicities and undertreatment seen in cancer patients. McCune
et al. [2] estimated that, of the population of patients taking chemotherapeutic drugs and CAM, at least 27% were
at risk for developing clinically relevant CAMdrug interactions. It is therefore of utmost importance that treating
oncologists are aware of the possibility and consequences
of CAMdrug interactions. This review provides more
information about currently known, clinically relevant PK
CAMdrug interactions in oncology, with a focus on the
mechanisms and clinical implications of enzyme induction.
The accompanying article by Tascilar et al. [3] in this issue
of The Oncologist describes overall clinical implications
of CAM use by cancer patients
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HerbDrug Interactions in Oncology
cassette (ABC) family of drug transporters like P-glycoprotein (Pgp, ABCB-1), breast cancer resistance protein
(BCRP, ABCG-2), multidrug resistance associated protein 1 (MRP-1, ABCC-1), and MRP-2 (ABCC-2) (Table 2).
These transporters are involved in the oral bioavailability
and hepatobiliary, direct intestinal, and urinary excretion of chemotherapeutics and their metabolites (Table 2)
[1618]. Increased expression of transporters is also one of
the pathways responsible for multidrug resistance of cancer
cells [18].
PK interactions between CAM and oncolytic drugs
occur when CAM, or the active constituents of CAM,
inhibit or induce the metabolizing enzymes or drug transporters involved in the PK disposition of chemotherapeutic
drugs (Tables 1, 2). Inhibition occurs when CAM are able
to decrease the normal activity level of a metabolic enzyme
or drug transporter via a competitive or noncompetitive
mechanism. Induction is a much slower process, in which
CAM increase the mRNA and protein levels of the relevant
metabolizing enzyme or drug transporter. This process is
reversible, and enzyme levels are reduced to normal if CAM
use is discontinued. CAM-induced PK changes can lead to

significant clinical effects in cancer patients, like a lower
therapeutic efficacy or greater toxicity of the chemotherapeutic drug [15, 19]. In the example of SJW and irinotecan or imatinib, induction of the enzymes involved in the
metabolism and transport of these chemotherapeutic drugs
is responsible for the lower plasma levels. SJW has been
shown to induce both CYP3A4 as well as Pgp in vitro and
in vivo [2022] and CYP2C19 in healthy subjects [8]. From
the other clinically relevant interaction, grapefruit juice
with etoposide, it is known that grapefruit juice is a potent
inhibitor of intestinal CYP3A4. Based on this fact, a greater
AUC of the CYP3A4 substrate etoposide would have been
expected after oral intake of the drug combined with grapefruit juice. However, in the patients studied, a lower AUC
of etoposide was observed. The explanation given by the
authors for this lower AUC was a possible inductive effect of
grapefruit juice on Pgp-mediated transport of etoposide [9].
In general, CYP inhibition will lead to higher levels of
the cytotoxic drug, causing recognizable, greater toxicity, unless the cytotoxic drug is an inactive prodrug such as
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Figure 1. The effect of hyperforin on irinotecan therapy. Hyperforin, the active constituent of St. Johns wort, binds to and activates the pregnane X receptor (PXR). Upon activation, PXR forms a heterodimer with the 9-cis retinoic acid receptor (RXR), and
this complex binds to the xenobiotic response elements (PXRE) in the cytochrome P450 3A4 (CYP3A4) gene. The transcription of
the gene is increased, and more CYP3A4 is formed, thereby increasing the metabolism of irinotecan into an inactive metabolite,
oxidized irinotecan. The amount of irinotecan left to be metabolized into SN-38 decreases, leaving less active SN-38 and a lower
therapeutic efficacy of irinotecan.
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Table 1. Metabolizing enzymes involved in the metabolism of chemotherapeutic drugs [15, 8587]
Metabolizing enzyme
Cytochrome P450 enzymes
CYP1A1, CYP1A2
CYP2A6
CYP2B6
CYP2C8
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A4
Dacarbazine
Cyclophosphamide, ifosfamide, tegafur
Cyclophosphamide, ifosfamide
Cyclophosphamide, ifosfamide, paclitaxel
Cyclophosphamide, ifosfamide
Teniposide
Tamoxifen, doxorubicin, vinblastine
Dacarbazine
Teniposide, etoposide, epipodophyllotoxin, cyclophosphamide, ifosfamide, vindesine,
vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, irinotecan, tamoxifen,
tipifarnib, gefitinib, imatinib
Etoposide, tipifarnib
Phase II enzymes
N-acetyltransferase 2
Glutathion S-transferase
Sulfotransferases
Thiopurine methyltransferase
Uridine diphosphate
glucuronosyltransferase
Amonafide
Busulfan, etoposide, doxorubicin, carboplatin, cisplatin, cyclophosphamide, thiotepa
Tamoxifen, mitomycin C
6-Mercaptopurine, 6-thioguanine
Irinotecan, epirubicin, topotecan, etoposide, flavopiridol, tipifarnib
Other
Carboxylesterase CES2
Dihydropyrimidine
dehydrogenase
Irinotecan
5-Fluorouracil, capecitabine
Table 2. ATP-binding cassette drug transporters involved in the transport of chemotherapeutic drugs [17, 18, 86]
Drug transporter
P-glycoprotein
(ABCB-1, MDR-1)
Chemotherapeutic drug
Actinomycin D, daunorubicin, docetaxel, doxorubicin, etoposide, irinotecan, mitoxantrone,
paclitaxel, teniposide, topotecan, vinblastine, vincristine, tamoxifen, mitomycin C, tipifarnib,
epirubicin, bisantrene
MRP-1 (ABCC-1)
Etoposide, teniposide, vincristine, vinblastine, doxorubicin, daunorubicin, epirubicin,
idarubicin, topotecan, irinotecan, mitoxantrone, chlorambucil, methotrexate, melphalan
MRP-2 (ABCC-2)
SN-38G (irinotecan metabolite), methotrexate, sulfinpyrazone, vinblastine
BCRP (ABCG-2, MXR)
9-Aminocamptothecin, daunorubicin, epirubicin, etoposide, lurtotecan, mitoxantrone, SN-38
(irinotecan metabolite), topotecan
Abbreviations: ABC, ATP-binding cassette; BCRP, breast cancer resistance protein; MDR, multidrug resistance gene; MRP,
multidrug resistance-associated protein; MXR, mitoxantrone resistance-associated protein.
cyclophosphamide or ifosfamide. For detailed information

about CAMdrug interactions resulting from inhibition, the
reader is referred to some recent reviews [1014, 23]. Summarized, CAMs that have already been shown to actively
inhibit CYP enzymes are: garlic [23], constituents of
Ginkgo biloba [23, 24], kava [23], ginseng [25], Echinacea
purpurea [24], milk thistle (silybin) [2628], and evening
primrose oil (cis-linoleic acid) [23]. Pgp activity was shown
to be inhibited by curcumin, ginsenosides, piperine, some

cathechins from green tea, quercetin, and silymarin [14, 29,
30]. Genistein is a substrate of BCRP and therefore acts as a
competitive inhibitor of BCRP-mediated transport [31].
Induction of CYP or drug transporters will, in the
case of active parent drugs, often lead to therapeutic failure because of lower plasma levels of the chemotherapeutic drug. As therapeutic failure in the treatment of cancer
CYP3A5
Chemotherapeutic drug
746
Nuclear Receptors
Recently, orphan nuclear receptors involved in the induction of metabolizing enzymes and ABC drug transporters
have been identified: the pregnane X receptor (PXR), the
constitutive androstane receptor (CAR), and the vitamin Dbinding receptor (VDR). After activation by endogenous or
exogenous ligands, these receptors form heterodimers with
the 9-cis retinoic acid receptor (RXR) and bind to xenobiotic
response elements in the target genes [32, 33]. Because of
this, the transcription of the target genes is increased, leading to detoxification and elimination of xenobiotics (Fig. 1).
PXR, also known as the steroid and xenobiotic receptor
(SXR) [33] or human proteinase-activated receptor (hPAR)
[34], has emerged as one of the main transcriptional regulators of CYP3A4 and Pgp [35, 36]. However, other metabolizing enzymes and drug transporters were also shown to
be under transcriptional control of PXR: CYP2B6 [37],
CYP2C9 [38], sulfotransferase (SULT) [39], UGT1A1
[40], glutathione S-transferases (GST) [41], and MRP-2
[42]. Currently known ligands of human PXR are all wellestablished inducers of CYP3A4, such as the drugs rifampicin, dexamethasone, clortrimazole, and paclitaxel [43,
44]. Moore et al. [45] showed that the inductive capacity of
SJW is also mediated by PXR. SJW, in particular its active
component hyperforin, activates PXR, thereby inducing
CYP3A4 and CYP2C9 expression (Fig. 1) [38, 45]. Hyperforin was also shown to form a complex with the ligandbinding domain of human PXR [46]. These data indicate
that the activation of PXR is one of the main mechanisms
behind induction of metabolizing enzymes and drug transporters by CAM.
Another nuclear receptor identified to be involved in the
induction of metabolizing enzymes is CAR. Although the
CYP2B gene is the main target of CAR, expression of other
hepatic genes, such as UGT1A1 and CYP2C9 among others, is also influenced by CAR [40, 4749]. Very recently, it
was shown that CAR is also involved in the regulation of the
multidrug resistance gene 1 (MDR-1) [50].
While PXR was shown to mainly regulate CYP3A4
expression and CAR to regulate CYP2B expression, there
is ample evidence that this specificity is not absolute and
that both the nuclear transcription function as well as the
ligand-binding capacity of these two receptors show some
overlap. VDR is the receptor that normally mediates cell
growth, differentiation, and death in response to 1,25dihydroxy vitamin D3. Schmiedlin-Ren et al. [51] were
the first to show that the VDR receptor is also involved in
the regulation of CYP3A4, and currently it is known that
VDR is also able to induce the expression of CYP2B6 and
CYP2C9 [52]. Ligands of VDR are the already mentioned
1,25-dihydroxy vitamin D3 and also the secondary bile
acid litocholic acid, indicating an important role of VDR in
the detoxification of hepatotoxic bile acids [53].
Methods to Measure Induction and

Activation of Nuclear Receptors by CAM
The role of PXR, CAR, and VDR in the induction of
metabolizing enzymes and drug transporters is now evident. Binding of CAM to any of these receptors can lead
to increased metabolism or transport of coadministered
chemotherapeutic drugs, leading to decreased therapeutic
efficacy or increased toxicity of prodrugs. This knowledge
has been applied to develop more specific methods to study
the inductive capacity of CAM in in vitro or in vivo model
systems [5458].
In the past, the fact that several compounds could induce
metabolizing enzymes or drug transporters was recognized, and primary cultures of hepatocytes have been used
for a long time to screen for the inductive potential of compounds. However, the main drawbacks of the use of human
hepatocytes are the availability, quality, and interindividual variation of human liver tissue. Further, this system
only gives information about the induction capacity and not
about the nuclear receptor involved [54, 55, 58].
In vivo models, using wild-type laboratory animals,
are not an alternative because of the observed species
differences in the ligand-binding domains (LBDs), especially in the LBD of PXR. Alternatively, transgenic animals that possess human versions of nuclear receptors
could be used [57].
Cloning of the human version of PXR [3335] led to the
development of competition binding assays and cell-based
reporter assays (Fig. 2). In a cell-based reporter assay,
expression plasmids for the specific full-length receptors,
PXR, VDR, or CAR, are cotransfected with a relevant
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is common, very often this effect may not be recognized

as the consequence of an interaction with CAM. Only just
recently, the mechanisms behind induction of metabolizing enzymes and drug transporters were discovered, and
this knowledge has led to new possibilities for the identification of CAM capable of causing induction. So, although
CAMdrug interaction based on inhibition processes can
be of clinical importance in oncology, this review further
focuses on how the mechanistic knowledge about induction processes can be an aid in the prediction of clinically
relevant CAManticancer drug interactions. It also gives
an overview of the current knowledge about the induction
capacity of CAM. Ultimately, more information about the
inductive potential of CAM can prevent undertreatment of
cancer patients and unacceptable side effects resulting from
increased activation of prodrugs.
Inductive Capacity of CAM

Currently, data about the inductive capacity of CAM and
their interaction with nuclear receptors is scarce and mainly
focused on PXR. Further, there is a substantial lack of clinical information about the effect of CAM on the PK of anticancer drugs. The already mentioned interaction of SJW
with PXR is the best-known example, and significant clinical effects of this interaction have already been shown, not
only for anticancer drugs, but also for other drugs like amitriptyline, cyclosporine, and warfarin [60]. Still, some studies have been performed that investigated the effect of other
Figure 2. Cell-based reporter assay. An expression plasmid

containing the full-length receptor, pregnane X receptor
(PXR), is cotransfected with a reporter plasmid into a human
cell line. The reporter plasmid contains a PXR response element (PXRE) upstream of a reporter gene, luciferase or alkaline phosphatase. Upon binding of a ligand transcription of
the reporter gene is increased and can be detected. (Based on
Landes N, Pfluger P, Kluth D et al. Vitamin E activates gene
expression via the pregnane X receptor. Biochem Pharmacol
2003;65:269273; and Kliewer SA. Pregnane X receptor:
Predicting and preventing drug interactions. Thromb Res
2005;117:133136; discussion 145151.)
CAMs on nuclear receptor-mediated CAMdrug interactions, and from those studies, possible effects of CAM on
the PK of anticancer drugs can be derived.
In Vitro
In vitro studies have been performed to investigate the
potential of CAM to activate nuclear receptors and to
induce metabolizing enzymes. An overview of these studies is given in Table 3.
Raucy [61] used CYP3A4 mRNA analysis in primary
cultures of human hepatocytes of 17 individuals to test the
inductive properties of several flavonoids, including quercetin, resveratrol, and curcumin. Of these, only quercetin
produced accumulation of CYP3A4 mRNA. However,
when a reporter gene assay with hPXR was used, quercetin did not show a significant increase in luciferase activity,
suggesting that CYP3A4 was induced by mechanisms not
involving PXR. Herbs like grapeseed extract, ginseng, garlic, and kava-kava also increased CYP3A4 mRNA levels
in hepatocytes, but of these botanicals, only kava-kava produced enhanced luciferase activity [61]. The results of that
study clearly showed that some CAMs have the potential to
induce CYP3A4, although not always mediated via PXR.
Individual forms of vitamin E also activate gene expression via PXR. Zhou et al. [62] found that -, -, -, and tocotrienols, forms of vitamin E, but not -, -, -, and tocopherols specifically bind to and activate PXR. In that
study, it was shown, however, that the induction of target
genes was tissue specific: upregulation of CYP3A4, but not
UGT1A1 or MDR-1, in primary hepatocytes in contrast to
increased UGT1A1 and MDR-1, but not CYP3A4, expression in intestinal LS180 cells [62]. Another study, also using
a cell-based reporter system, showed that although - and tocotrienol showed the strongest inductive efficacy, -, -,
and -tocopherol could also activate PXR [63]. In that study,
exposure of HepG2 cells to -tocotrienol gave an upregulation of endogenous CYP3A4 and CYP3A5 mRNA.
Other studies using gene reporter assays or mRNA levels of CYP3A4 in human hepatocytes showed the potential
of several CAMs to induce CYP3A4 by activation of PXR:
Gugulipid, or its chemical constituents guggulsterones,
derived from the Mukul myrrh tree [6467], hops [64],
two traditional Chinese medicines (TCMs), Wu Wei Zi
(Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza
uralensis Fisch), and their selective constituents [68], carotenoids, especially -carotene, and retinol [69].
Flavonoids, like chrysin, induce UGT1A1 expression
via another receptor, the aryl hydrocarbon receptor (AhR),
which is beyond the scope of this review. However, PXR and
CAR were also shown to contribute to the overall UGT1A1
response to flavonoids [70].
reporter plasmid into a human cell line. This reporter plasmid contains either one or more copies of the response elements upstream of a heterologous promoter or an intact
promoter of a target gene (e.g., CYP3A4), coupled to a
reporter gene like alkaline phosphatase or luciferase [56,
59]. Advantages of the reporter gene assays are the use of
inexpensive human-derived cell lines and the possibility to
develop high-throughput formats. Reporter gene assays for
PXR to assess the CYP3A4 induction potential of xenobiotics were proven to be reliable and complementary to the use
of human hepatocytes [55].
These techniques can all be applied to test the inductive capacity of CAM, but ultimately, PK studies in patients
using CAM will give a definite answer about the effects of
CAM on the metabolism and excretion of chemotherapeutic drugs.
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Table 3. Potential of complementary and alternative medicines (CAM) to activate nuclear receptors and to induce metabolizing enzymes
Method
CYP3A4 cell-based reporter assay with PXR
mRNA expression in HepG2 cells
Apigenin
CYP3A4 mRNA expression in human hepatocytes

CYP3A4, CYP2C9, and MRP-2 cell-based reporter
assay with PXR
CYP3A4, CYP2C9, and MRP-2 mRNA expression
in human hepatocytes
Pharmacokinetics of warfarin in rats
Apo-carotenals
Curcumin
Gan Cao (TCM)
Garlic
Ginseng
Grapeseed extract
Guggulsterone
Hops
Kava-kava
Lycopene
Quercetin
Resveratrol
Retinol
Silymarin
Vitamin E
CYP3A mRNA expression in human and rodent

hepatocytes
Protein interaction assay
Pharmacokinetics of diltiazem and propranolol in
healthy volunteers
-, -, -, and -tocotrienols
Ligand-binding assay PXR
mRNA expression in primary hepatocytes
mRNA expression in LS180 cells
Effect
CAT activity
CYP3A4/3A5, MDR-1,
and MRP-2
No effect
No effect
CAT activity
No effect
No effect
luciferase activity
Study
Ruhl et al. [69]
Ruhl et al. [69]
expression
Mu et al. [68]
t1/2, AUC, clearance

CYP3A4 mRNA
No effect
CYP3A4 mRNA
No effect
CYP3A4 mRNA
No effect
luciferase activity
CYP3A mRNA
Mu et al. [68]
Raucy [61]
Raucy [61]
Raucy [61]
Raucy [61]
Raucy [61]
Raucy [61]
Brobst et al. [65],
Owsley and
Chiang [66]
Brobst et al. [65]
Direct interaction with PXR

Cmax, AUC
Brobst et al. [65]

Dalvi et al. [67]
luciferase activity
CYP3A4 mRNA
luciferase activity
No effect
CYP3A4 mRNA
No effect
No effect
No effect
CAT activity
CYP3A4/3A5, MDR-1,
and MRP-2
No effect
No effect
luciferase activity
CAT activity for and
Effective binding to PXR
CYP3A4, no effect on
UGT1A1 or MDR-1
MDR-1, UGT1A1, no
effect on CYP3A4
CYP3A4/3A5 by
No effect
CAT activity for , ,
No binding
luciferase activity
Kliewer et al. [64]

Raucy [61]
Raucy [61]
Ruhl et al. [69]
Raucy [61]
Raucy [61]
Raucy [61]
Raucy [61]
Ruhl et al. [69]
Ruhl et al. [69]
Raucy [61]
Raucy [61]
Ruhl et al. [69]
Raucy [61]
Raucy [61]
Mu et al. [68]
CAM
-carotene
Raucy [61]
Raucy [61]
Zhou et al. [62]
Landes et al. [63]
Zhou et al. [62]
Zhou et al. [62]
Zhou et al. [62]

Landes et al. [63]
Vitamin E
Zhou et al. [62]
-, -, -, and -tocopherols
Landes et al. [63]
Ligand-binding assay PXR
Zhou et al. [62]
CYP3A4, CYP2C9, and MRP-2 cell-based reporter
Mu et al. [68]
Wu Wei Zi
(TCM)
assay with PXR
CYP3A4, CYP2C9, and MRP-2 mRNA expression
Mu et al. [68]
expression
in human hepatocytes
Abbreviations: AUC, area under the concentrationtime curve; CAT, chloramphenicol acetyltransferase reporter gene activity;
CYP, cytochrome P450; Cmax, maximum observed concentration; MDR, multidrug resistance gene; MRP, multidrug resistanceassociated protein; PXR, pregnane X receptor; t1/2, half-life; TCM, traditional Chinese medicine; UGT, uridine diphosphoglucuronosyl transferase.
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In vivo
of modulation of another enzyme or drug transporter. However, differences in the composition of the active constituents of the garlic supplements used could also explain variation in the clinical results. Therefore, patients are advised
to use caution when combining garlic supplements with
saquinavir, but also with anticancer drugs metabolized by
CYP3A4 and transported by Pgp (Table 1, Table 2) [81].
Citrus aurantium, Panax ginseng, Echinacea purpurea,
milk thistle, and saw palmetto extracts taken by healthy
volunteers all had no effect on the activity of CYP3A4,
CYP1A2, CYP2E1, and CYP3A4 measured using model
substrates [77]. Milk thistle also did not influence the PK of
the protease inhibitor indinavir in two independent studies
[82, 83]. However, a recent study [84] showed that 8 days of
echinacea treatment in volunteers resulted in a 34% greater
systemic clearance of midazolam and a significantly lower
AUC. In contrast, the oral bioavailability of midazolam
after echinacea intake was significantly greater, indicating
that there is a difference in the effect between hepatic and
intestinal metabolism or drug transport. These data indicate that interactions of echinacea with anticancer drugs
that are substrates of CYP3A4 is likely (Table 1).
PK Studies in Humans
Besides the thorough investigation of the effects of SJW
on the PK of drugs [75], only a few other clinical studies
have been executed thus far that investigated interactions
between other CAM and (anticancer) drugs.
Ginkgo biloba, one of the most widely used herbal
products in the world, was shown to induce omeprazole
hydroxylation in a CYP2C19 genotype-dependent manner in healthy male subjects. The authors therefore suggest
that coadministration of Ginkgo biloba with omeprazole or
other CYP2C19 substrates, like teniposide (Table 1), may
significantly reduce their effects [76]. In two studies with
healthy volunteers or elderly patients, Ginkgo biloba had no
effect on the PK of model substrates for CYP3A4, CYP1A2,
CYP2E1, and CYP2D6 [77, 78].
In the same studies, there was also no significant effect
observed on the activity of metabolizing enzymes after
intake of garlic [77, 78]. Garlic intake also had no effect on
the metabolism of acetaminophen [79] and on the PK of
the protease inhibitor ritonavir in healthy volunteers [80].
However, intake by healthy volunteers of a higher dose of
garlic did have a significant impact on the PK of another
protease inhibitor, saquinavir [81]. In the presence of garlic,
the mean AUC of saquinavir was 51% lower and the mean
Cmax was 54% lower. Although saquinavir is mainly metabolized by CYP3A4 and transported by Pgp, the discrepancy
with the results obtained with model substrates and ritonavir suggests that the PK alterations with saquinavir are not
a result of induction of CYP3A4 but more likely are a result
Conclusion
As the intake of CAM is increasing, herbdrug interactions within oncology are likely to occur. In particular,
lower therapeutic efficacy resulting from induction of
metabolizing enzymes and drug transporters may not
be easily recognized. It is therefore important that treating physicians are aware of the possibility of CAMdrug
interactions. Unfortunately, the effects of CAMs on induction of metabolizing enzymes and drug transporters are
generally not known and poorly studied. Some investigators have used probe substrates to explore the effects of
herbs on the activity of specific CYP enzymes in healthy
volunteers, like Gurley et al. [77]. Suitable substrates are
caffeine for CYP1A2, tolbutamide for CYP2C9, mephenytoin for CYP2C19, dextrometorphan or debrisoquin for
CYP2D6, and midazolam or erythromycin for CYP3A4.
In addition, a cocktail of probe drugs can be used to
explore the activities of multiple CYP enzymes [19]. From
these type of studies, the physician already could derive
specific recommendations for the use of various herbs in
combination with chemotherapeutic treatment. However,
phenotyping studies do have some limitations, such as
marked intrasubject and intersubject variability and the
possibility of interaction between coadministered probes
[19]. Another disadvantage is the fact that, in most of
these studies, herbs were used for a relatively short period
of time, while for induction, in particular, chronic use is
important. Another point of concern is the extrapolation
Although, because of species differences, in vivo models are not the best way to study induction of metabolizing enzymes and drug transporters, information can be
obtained from them, especially when humanized transgenic animals are used [57]. In humanized CAR transgenic
mice, it was shown that the TCM Yin Zhi Huang, a decoction of Yin Chin (Artemisia capillaris) and three other
herbs, accelerates the clearance of bilirubin by activation of
CAR [71]. Studies with wild-type rats showed induction of
CYP2B by Ginkgo biloba extract [72], increased CYP3A
expression and activity after exposure to licorice root
extract and its natural constituent glycyrrhizin [73], and
enhanced activity of GST and UGT after intake of rooibos
(Aspalathus linearis) and honeybush (Cyclopia intermedia) teas [74]. These studies, however, give no information
about the mechanism behind the induction and the nuclear
receptor involved. Careful interpretation of in vivo results
is thus necessary because the species differences in nuclear
receptors and inductive processes make extrapolation to
humans difficult.
749
750
receptors, CAR and VDR, as these are also an integral part

of the mechanism of inductive processes. In the end, there
is almost no information about whether the commonly
applied dose range of CAM is critical for anticancer drug
interactions in patients. Evaluation of the data obtained
with in vitro and in vivo methods in well-designed clinical
trials is therefore of utmost importance. Further research
is therefore required and has to be encouraged to elucidate
the role of CAM in unwanted drug interactions to prevent
undertreatment of cancer patients or unexpected toxicities, and to establish guidelines for CAM use. For now,
oncologists have to be encouraged to discuss CAM use
with their patients and to be aware of possible CAManticancer drug interactions. In some cases, especially with
the well-studied SJW, physicians should advise patients to
refrain from their CAM use.
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See also Complementary and Alternative Medicine During

Cancer Treatment: Beyond Innocence,
by Metin Tascilar, Floris A. de Jong, Jaap Verweij, and Ron H.J. Mathijssen, on p. 732.
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Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction

Irma Meijerman, Jos H. Beijnen and Jan H.M. Schellens
Oncologist 2006;11;742-752
DOI: 10.1634/theoncologist.11-7-742
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