Current Drug Metabolism, 2011, 12, 000-000

Metabolic Drug Interactions between Antidepressants and Anticancer Drugs: Focus

on Selective Serotonin Reuptake Inhibitors and Hypericum Extract
Filippo Caraci1, Rosalia Crupi2, Filippo Drago3 and Edoardo Spina2,4
1

Department of Pharmaceutical Sciences, University of Catania, 2Section of Pharmacology, Department of Clinical and Experimental
Medicine and Pharmacology, University of Messina, 3Department of Clinical and Experimental Medicine and Pharmacology, University of Catania, 4IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy
Abstract: Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation
antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum
extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes
(CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug, such as tamoxifen, by decreasing
the formation of active metabolites of this drug. Women with breast cancer who receive paroxetine in combination with tamoxifen are at
increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely
to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by
inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as
imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the
use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.

Keywords: Anticancer drugs, antidepressants, cytochrome P450 system, drug interaction, enzyme inhibition, enzyme induction, Hypericum
extract.
INTRODUCTION
Major depression and depressive disorders are associated with
significant disability, impaired quality of life and reduced survival.
Individuals with cancer are at increased risk for persistent depressive disorders compared to the general population [1, 2]. The incidence of depression in cancer patients is estimated to be in the
range of 1.5%57%, depending on the disease severity, the method
of assessment and level of patient disability [3]. Although depressive disorders are common among people with cancer, they are frequently underdiagnosed and undertreated, in particular depressive
symptoms in women with breast cancer [4, 5]. Untreated depression
in the presence of comorbid conditions may result in more frequent
clinic visits, increased costs, extended hospitalization, and finally
reduced compliance and quality-of-life.
Cancer patients diagnosed with mild to severe depression may
benefit from a multimodal approach that includes both psychotherapeutic and pharmacologic interventions. Antidepressant medications used in cancer patients are quite similar to those used in the
primary care setting and include older and newer compounds [6]
(Table 1). Newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake
inhibitors (SNRIs), have largely replaced older antidepressants as
first-line drugs due to a more advantageous tolerability and safety
profile. A small number of studies have been conducted to assess
the clinical efficacy of antidepressant drugs in the treatment of cancer patients with depressive disorders [7]. These studies suggest an
efficacy of SSRIs compared to placebo in treating depression in
cancer patients with fewer side effects as compared to tricyclics [5,
8]. Recently the herbal extract of Hypericum perforatum, commonly called St. John's Wort (SJW), has become one of the worlds
most popular herbal preparations, particularly among cancer

Table 1.

Classification of Antidepressant Drugs. (Based on

ref. 6)

OLDER or FIRST-GENERATION ANTIDEPRESSANTS

Monoamine oxidase inhibitors (MAO-I)
- phenelzine, tranylcipromine, moclobemide
Tricyclic antidepressants (TCA)
- amitriptyline, imipramine, clomipramine, nortriptyline, desipramine,
trimipramine, doxepin,
dothiepin, maprotiline
NEWER or SECOND-GENERATION ANTIDEPRESSANTS
Selective serotonin reuptake inhibitors (SSRI)
- fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram
Serotonin and noradrenaline reuptake inhibitors (SNRI)
- venlafaxine, duloxetine, milnacipran
Noradrenaline reuptake inhibitors (NARI)
- reboxetine
Noradrenergic and specific serotonergic antidepressants (NASSA)
- mirtazapine
Serotonin antagonist/reuptake inhibitors (SARI)
- trazodone, nefazodone
Noradrenaline and dopamine reuptake inhibitors (NDI)
- bupropion
Melatonergic agents

*Address correspondence to this author at the Section of Pharmacology,

Department of Clinical and Experimental Medicine and Pharmacology,
University of Messina, Policlinico Universitario, Via Consolare Valeria
98125 Messina, Italy; Tel: +39 090 2213647; Fax: +39 090 2213300;
E-mail espina@unime.it
1389-2002/11 $58.00+.00

- agomelatine

2011 Bentham Science Publishers Ltd.

2 Current Drug Metabolism, 2011, Vol. 12, No. 5

patients, because of its similar efficacy and tolerability compared to

SSRIs in mild to moderate forms of depression [9-12]. Nevertheless the intake of Hypericum extracts often remains unrecognized
by physicians resulting in both clinically relevant pharmacokinetic
drug interactions and reduced clinical efficacy of anticancer drugs
[13].
Patients with cancer who concurrently receive antidepressants and anticancer drugs are at particularly high risk of drugdrug interactions, because they commonly receive multiple medications, including cytotoxic chemotherapy, hormonal agents and supportive care drugs [14, 15]. Drug interactions are known to cause
approximately 2030% of all adverse drug reactions and can also
be a common cause of morbidity and mortality in cancer patients
[16]. It is therefore fundamental for clinicians to be aware of the
potential drug interactions between agents that are used within the
oncology setting and those antidepressants that are commonly used
for the management of depressive disorders, in order to prevent
unwanted toxicities, inadequate drug exposures or alternatively to
avoid a drug-drug interaction which can lead to a reduced clinical
efficacy of anticancer drugs.
In the present article we review the current literature on clinically relevant metabolic drug interactions between antidepressants
and anticancer drugs. A variety of chemotherapeutic agents may be
used in oncology patients. A list of anticancer drugs is shown in
Table 2 [15]. Although many potential drug interactions can theoretically occur between antidepressants and anticancer drugs, we
have focused this review only on the currently available evidence
for clinically significant interactions between certain antidepressants, namely SSRIs and Hypericum extracts, and antineoplastic
agents.

Caraci et al.

Table 2.

Classification of Anticancer Drugs. (Based on Ref.

15)

Alkylating agents
- busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide,
lomustine, trofosfamide
Antimetabolites
- capecitabine, cytarabine, fluorouracil, gemcitabine, methotrexate, pemetrexed
Antimicrotubules
- docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine
Biological modifiers
- filgrastim, interferon-

Corticosteroids
- dexamethasone, methylprednisolone, prednisolone, prednisone
Hormone antagonists
- anastrazole, exemestane, flutamide, letrozole, tamoxifen, toremifene
Topoisomerase inhibitors
- doxorubicin, epirubicin, idarubicin, etoposide, teniposide, irinotecan,
topotecan, mitoxantrone
Tyrosine kinase inhibitors
- dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib,
sunitinib
Monoclonal antibodies

POTENTIAL FOR CLINICALLY RELEVANT METABOLIC

INTERACTIONS BETWEEN ANTIDEPRESSANT AND
ANTICANCER DRUGS
Pharmacokinetic interactions occur when one drug influences
the absorption, distribution, metabolism, and/or excretion of another one. Most pharmacokinetic interactions with antidepressants
and anticancer drugs occur at a metabolic level and usually involve
the hepatic cytochrome P450 (CYP) isoenzymes which are responsible for the oxidation of most drugs, environmental toxins and endogenous substrates [17]. The major CYP enzymes involved in
drug metabolism include CYP1A2, CYP2B6, CYP2C9, CYP2C19,
CYP2D6 and CYP3A4. The activity of these isoenzymes is genetically determined and may be influenced by pathophysiological and
environmental factors, including concomitant administration of
other drugs. CYP-mediated drug interactions generally result from
either enzyme inhibition or enzyme induction [18, 19]. In recent
years, characterization of the isoenzymes involved in the metabolism of individual drugs and identification of substrates, inhibitors,
and inducers of different CYPs have greatly improved the prediction of metabolic interactions. In particular, provides an invaluable
resource in helping to anticipate potential interactions. As shown in
Table 3, the majority of commonly used antidepressant and anticancer drugs are extensively metabolized by CYP enzymes and
some of these may also act as inhibitors or inducers of one or more
of these isoforms [13, 15, 20-29]. As many compounds of these two
therapeutic classes share common metabolic pathways, potential
CYP-mediated drug interactions may be anticipated. In theory, concomitant treatment of antidepressant and anticancer drugs metabolized by the same enzyme or coadministration of an anticancer drug
with an antidepressant acting as inhibitor or inducer, or viceversa,
involves the risk of a drug interaction. This does not necessarily
imply that this potential interaction is clinically relevant. The clinical implications of a potential metabolic interaction are dependent
on several drug- and patient-related factors [20, 30]. Issues related
to the characteristics of the drugs include the therapeutic window

- bortezomib, cetuximab, rituximab, trastuzumab

Others
- bleomycin, cisplatin, thalidomide

(interactions affecting drugs with a narrow therapeutic index are

more likely to be clinically relevant than those involving drugs with
a wider margin of safety), the potency and the concentration of the
inhibitor/inducer, the contribution of the affected enzyme to overall
drug elimination and the presence of pharmacologically active metabolites. With regard to patient-related factors, an important role is
played by genetic predisposition, ethnicity, age (i.e., elderly patients
are more susceptible to interactions) and co-morbidity. These concepts have to be taken into account when evaluating the potential
for metabolic drug interactions between antidepressant and anticancer drugs.
As antidepressants undergo extensive metabolism via the hepatic CYP system, concomitant treatment with other medications,
including anticancer agents, acting as inhibitors or inducers of the
enzymes involved in their biotransformation, may cause changes in
antidepressant plasma concentrations. However, due to the relatively wide margin of safety of second-generation antidepressants,
the clinical consequences of such kinetic modifications are unlikely
to be relevant [20, 31]. On the other hand, newer antidepressants
have a high potential to cause metabolically-based drug interactions
due to their inhibitory effect on CYP activity [20, 23, 24, 31] (see
Table 3). In vitro and in vivo evidence clearly indicates that newer
antidepressants are not equivalent in their potency of inhibition of
various CYP isoenzymes [20, 23, 24, 31].
Fluoxetine and its metabolite norfluoxetine are potent inhibitors
of CYP2D6 and moderate inhibitors of CYP2C9, while they affect
mildly to moderately the activity of CYP2C19 and CYP3A4 [24].
Paroxetine is a potent in vitro inhibitor of CYP2D6, while it affects
only minimally the activity of other CYP isoforms [24]. Fluvoxamine markedly inhibits CYP1A2 and CYP2C19 [24, 32]. Duloxetine

Drug Interactions between Antidepressants and Anticancer Drugs

is a moderate inhibitor of CYP2D6, while sertraline inhibits this

isoform in a dose-dependent manner [33]. Therefore, clinically
relevant interactions may occur when these antidepressants are coadministered with substrates of these isoforms, especially compounds with a narrow therapeutic index, such as most anticancer
drugs. These interactions may cause an increase in serum chemotherapeutic drug concentrations or, alternatively, reduce the formation of active metabolites of anticancer drugs which are predominantly formed via CYP-mediated metabolism (e.g. endoxifen
and hydroxytamoxifen). Other second-generation antidepressants
including citalopram, escitalopram, venlafaxine, mirtazapine and
reboxetine possess a weak inhibitory effect on different CYP isoforms in vitro and appear to have a more favorable drug interaction
profile also in vivo [24, 34-36]. By contrast, Hypericum extracts
may induce CYP isoforms, in particular CYP3A4, which is responsible, at least in part, for the biotransformation of several antineoplastic agents [37]. Therefore, coadministration of Hypericum extracts with anticancer drugs metabolized via CYP3A4 may increase
their rate of metabolism, thereby resulting in lower plasma drug
concentrations and, possibly, a loss of clinical efficacy. Conversely,
if the affected drug has an active metabolite, induction may lead to
increased metabolite concentrations and, possibly, enhanced pharmacological or toxicological activity.
Anticancer drugs are subject to extensive oxidative metabolism
in the liver. Differently from newer antidepressants, these agents
generally have a narrow therapeutic index. Therefore even a slight
increase or decrease in cytotoxic activity due to a drugdrug interaction could result in excessive toxicity or reduced efficacy. Because the inhibitory effect of second-generation antidepressants on
the CYP isoenzymes is concentration dependent, the potential for
drug interactions may be higher in cancer patients, who can have
underlying hepatic and renal impairments which may result in a
reduced rate of drug elimination. On the other hand, in vitro evidence indicates that anticancer drugs can interfere with CYP
system not only as substrates, but also inhibiting or inducing
CYP isoenzymes (see Table 3) [15, 25]. In this respect, several
members of the recently developed and approved class of tyrosine
kinase inhibitors can also directly inhibit different CYP isoenzymes
(see Table 3) [15, 25]. In particular, imatinib is a competitive inhibitor of the CYP3A4, CYP2C9 and CYP2D6 isoenzymes, sorafenib inhibits CYP2B6, CYP3A4, CYP2C19 and CYP2D6, gefitinib
inhibits both CYP2C19 and CYP2D6 isoenzymes, whereas
dasatinib and erlotinib inactivate CYP3A4 in a time- and concentration-dependent manner [15, 25]. These tyrosine kinase inhibitors
can then theoretically cause clinically relevant drug interactions
with other anticancer drugs metabolized by the same CYP isoenzymes (see Table 3).
Although many potential drug interactions can theoretically occur between antidepressants and anticancer drugs, based on these
considerations, a clinically relevant metabolic interaction can be
expected when a drug with a low therapeutic index, such as many
antineoplastic drugs, is coadministered with a potent inhibitor (e.g.
some SSRIs) or inducer (e.g. Hypericum extracts) of the major
pathway of its metabolism. Consistent with this, most of the available kinetic studies regard clinically relevant metabolic interactions
between SSRIs or Hypericum extracts with certain chemotherapeutic agents.
METABOLIC INTERACTIONS BETWEEN SSRI AND TAMOXIFEN
A well documented and potentially clinically relevant interaction may occur between certain SSRIs and tamoxifen [38].
Tamoxifen is a selective estrogen receptor modulator used in the
treatment and prophylaxis of breast cancer [39]. Over the past 40
years tamoxifen has reduced the risk of recurrence by about onehalf and the risk of breast cancer death by about one-third. Tamoxifen is a prodrug that is metabolized by the hepatic CYP system

Current Drug Metabolism, 2011, Vol. 12, No. 5

to the active metabolites 4-hydroxytamoxifen and 4-hydroxy-Ndesmethyltamoxifen (endoxifen) [40]. Both metabolites have an
affinity for estrogen receptor that is 100-fold higher than the parent
compound. However, endoxifen is considered the most important
metabolite as its plasma concentrations are several times higher
than those of 4-hydroxytamoxifen (Fig. 1). The biotransformation
of tamoxifen to endoxifen is catalyzed mainly by polymorphic
CYP2D6 (Fig. 1) Evidence that this isoform is a determinant of tamoxifen efficacy and tolerability has been supported by studies
showing that patients with breast cancer who were poor metabolizers of CYP2D6 had a worse clinical outcome (increased recurrence
and mortality rates) and fewer adverse effects than those who were
extensive metabolizers [41-45]. Therefore, coadministration of
drugs that inhibit CYP2D6 may reduce the clinical benefit of tamoxifen by decreasing the formation of its active metabolite, particularly when these agents are used for an extended period. It is
estimated that 20%-30% of women taking tamoxifen are also
treated with antidepressants. This includes not only patients with
breast cancer with co-morbid depression or anxiety, but also those
receiving antidepressants for the treatment of vasomotor instability
(hot flashes), a frequent complication of tamoxifen treatment. In
this respect, several trials have documented that certain antidepressants, particularly SSRIs and venlafaxine, are effective in the management of hot flashes [46]. As newer antidepressants may inhibit
CYP2D6 activity, it can be hypothesized that coadministration of
these agents may decrease the formation of tamoxifen metabolites
with increased risk of relapse of breast cancer.
In a preliminary prospective study, Stearns et al. [47] measured
plasma concentrations of tamoxifen and its metabolites in 12
women with breast cancer who were taking adjuvant tamoxifen, at a
dose of 20 mg/day, before and after 4 weeks of paroxetine coadministration at a dose of 10 mg/day. A statistically significant decrease in plasma concentrations of the active metabolite endoxifen
from a mean 12.4 ng/ml to 5.5 ng/ml (p<0.01) was observed. In a
subsequent study, plasma concentrations of endoxifen were measured in 80 women treated with tamoxifen, 20 mg/day, genotyped
for CYP2D6, 24 of whom were taking CYP2D6 inhibitors [48].
After 4 months of tamoxifen treatment, plasma concentrations of
endoxifen were significantly lower in subjects with a CYP2D6 homozygous variant genotype or a heterozygous genotype than in
those with a homozygous wild-type genotype. Among subjects with
a homozygous wild-type genotype, plasma endoxifen concentrations were slightly reduced in women taking venlafaxine, a weak
inhibitor of CYP2D6, moderately decreased in women receiving
sertraline, a weak to moderate inhibitor of CYP2D6, and were substantially reduced in women treated with paroxetine, a potent inhibitor of CYP2D6. A prospective trial of 158 patients with breast
cancer taking tamoxifen confirmed these findings: concomitant use
of potent inhibitors of CYP2D6, such as paroxetine and fluoxetine,
significantly decreased mean plasma endoxifen concentrations, coadministration with weak inhibitors of CYP2D6, such as sertraline
and citalopram, resulted in a slight reduction of plasma endoxifen
concentrations, while simultaneous treatment with venlafaxine did
not appear to affect the metabolite concentrations [49].
Over the past few years, different pharmacoepidemiological
studies have investigated the potential clinical relevance of the interaction between SSRIs and tamoxifen. Retrospective, populationbased, case-control or cohort studies evaluating the impact of antidepressant treatment on breast cancer recurrence in women taking
tamoxifen have yielded mixed results [50-57]. Most of these investigations found no association between antidepressant use and the
risk of recurrence, either in general or for specific types of antidepressants [50-56]. However, in some of these studies the number of
observations was too small to achieve significance [50, 51]. Four
case-control, retrospective studies based on data from the Danish
Breast Cancer Cooperative Group, found no increased risk of breast
cancer recurrence in women on tamoxifen and concomitant citalo-

4 Current Drug Metabolism, 2011, Vol. 12, No. 5

Table 3.

Antidepressants and Anticancer Drugs Acting as Substrates, Inhibitors and Inducers of the Major Drug Metabolizing Cytochrome P450 Isozymes. (Based on ref. 13, 15, 20-29)

Enzymes
CYP1A2

Caraci et al.

Substrates

Inhibitors

Antidepressants

Antidepressants

amitriptyline, clomipramine, imipramine, fluvoxamine, duloxetine, mirtazapine,

fluvoxamine1

agomelatine

Anticancer drugs

Anticancer drugs

anastrazolea

Inducers

erlotinib, flutamide, imatinib, tamoxifen, thalidomide

CYP1A2 is responsible for the metabolic activation of numerous promutagens and
procarcinogens
CYP2B6

CYP2C9

CYP2C19

CYP2D6

Antidepressants
bupropion

Anticancer drugs

Anticancer drugs

cyclophosphamidea, ifosfamidea,

cyclophosphamide, ifosfamide

sorafeniba

Antidepressants

Antidepressants

fluoxetine

fluoxetine2, fluvoxamine2

Anticancer drugs

Anticancer drugs

Anticancer drugs

cyclophosphamidea,

anastrozole, carmustine, cyclophosphamide, idarubicin, imatinib, tamoxifen

anastrazolea, imatiniba

ifosfamidea

Antidepressants

Antidepressants

amitriptyline, clomipramine, imipramine, citalopram, escitalopram

fluvoxamine1, fluoxetine2

Anticancer drugs

Anticancer drugs

tamoxifen, cyclophosphamide, lapatinib, leflunomide, thalidomide

gefitiniba, letrozolea, sorafeniba

Antidepressants

Antidepressants

amitriptyline, clomipramine, imipramine, desipramine, nortriptyline,

fluoxetine1, paroxetine1,

fluoxetine, paroxetine, fluvoxamine, citalopram, escitalopram, duloxetine,

venlafaxine, mirtazapine

sertraline2, bupropion2, duloxetine2

Anticancer drugs

citalopram3, escitalopram3

cyclophosphamide, idarubicin, imatinib, tamoxifen. vinblastine, vincristine,

Anticancer drugs

vinorelbine

idarubicina, imatiniba, gefitiniba ,

sorafeniba

CYP3A4

Antidepressants

Antidepressants

Antidepressants

amitriptyline, clomipramine, imipramine, sertraline, citalopram, escitalopram,

nefazodone1, fluoxetine2,

hypericum extract

venlafaxine, mirtazapine, nefazodone

fluvoxamine

Anticancer drugs

Anticancer drugs

cyclophosphamidea,

prednisolone, prednisone), cyclophosphamide, cytarabine, dasatinib, erlotinib,

anastrazole , cytarabine ,
dasatiniba,

ifosfamidea, dexamethasonea,

exemestane, ifosphamide, trofosfamide, letrozole, docetaxel, paclitaxel,

erlotiniba, imatinib1,, irinotecana

erlotiniba

etoposide, teniposide, gefitinib, imatinib, lapatinib, nilotinib, irinotecan,

sorafeniba, tamoxifena

anastrazole, busulfan, corticosteroids (dexamethasone, methylprednisolone,

Anticancer drugs
a

doxorubicin, sorafenib, sunitinib, tamoxifen, toremifene, vinblastine,

vincristine, vinorelbine
1

Potent inhibition; 2Moderate inhibition; 3Weak inhibition; aIn vitro studies

pram, escitalopram [52, 53] or CYP2D6-inhibiting medications including various antidepressants [54, 55]. However, in these studies
the majority of exposed cases were treated with antidepressants
which are weak CYP2D6 inhibitors or non-inhibitors (citalopram,
escitalopram, venlafaxine, mirtazapine). A recently published observational study, performed in the Netherlands, showed no association between concomitant use of CYP2D6 inhibitors, mainly

fluoxetine or paroxetine, and breast cancer recurrence in patients

treated with tamoxifen [56]. By contrast, a recent retrospective,
population-based cohort study evaluated whether the use of SSRIs
is associated with adverse outcomes in elderly women aged 65 or
older treated with tamoxifen [57]. By the use of a large cancer registry and other healthcare data in Ontario, it was documented that
women with breast cancer who received paroxetine in combination

Drug Interactions between Antidepressants and Anticancer Drugs

Current Drug Metabolism, 2011, Vol. 12, No. 5

Fig. (1). A simplified scheme for tamoxifen metabolism in man.

The active metabolites of tamoxifen (TAM), endoxifen and hydroxytamoxifen, are predominantly formed via CYP2D6-mediated metabolism [40]. The
relative contribution of each pathway to the overall oxidation of TAM is shown by the thickness of the arrow. The primary pathway of metabolism from tamoxifen to endoxifen is first N-demethylation by CYP3A4 to N-desmethyl-tamoxifen, followed by hydroxylation by CYP2D6. Coadministration of SSRIs that
strongly inhibit CYP2D6, such as paroxetine and fluoxetine, may reduce the clinical benefit of tamoxifen by decreasing the formation of endoxifen.

with tamoxifen were at increased risk for death from breast cancer
and death from any cause. In particular, absolute increases of 25%,
50% and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54% and 91%
relative increases in the risk of death from breast cancer, respectively (p<0.05 for each comparison). On the other hand, no increased risk of breast cancer mortality was associated with exposure
to the other SSRIs during tamoxifen treatment. These findings support the hypothesis that paroxetine may reduce or abolish the benefit of tamoxifen in women with breast cancer, presumably by inhibiting its CYP2D6-mediated bioactivation.
Desmerais and Looper [58] have recently reviewed the literature on the interactions between newer antidepressants and tamoxifen via CYP2D6. Based on the available studies and knowledge on the inhibitory effect of antidepressants on CYP2D6, they
provide treatment recommendations and suggest to avoid the use of
paroxetine, fluoxetine and bupropion, a new antidepressant that
moderately inhibits CYP2D6 activity, in women taking tamoxifen
for the treatment or prevention of recurrence of breast cancer.
METABOLIC INTERACTIONS BETWEEN HYPERICUM
EXTRACT AND ANTICANCER DRUGS
Extracts of Hypericum perforatum have been used for centuries
in herbal medicine and have been clinically studied since the early
1990s [9]. Current evidence appears to support the efficacy of Hypericum extract for the treatment of mild to moderate depression
[12] and also demonstrate a lower withdrawal due to adverse events
in patients treated with Hypericum extract compared to SSRI [11].
Nevertheless Hypericum extract, by influencing important drugmetabolizing enzymes and drug transporters, can alter the pharmacokinetics of many different drug classes including anticancer
drugs. Interactions of clinical relevance often relate to the potential
of Hypericum extract for inducing cytochrome P450 enzymes (particularly CYP3A4) and also increasing expression of P-glycoprotein
(P-gp), which exert a central role in the transport of several anticancer drugs [13,14, 59].
Available evidence suggests that SJW drug interactions can be
due to hyperforin, one of the main constituents of Hypericum extract, which induces the activation of the pregnane X receptor

(PXR). Once activated by hyperforin, PXR forms a heterodimer

with the retinoid X receptor (RXR) and then promotes the expression of different genes such as P-gp, CYP3A4, CYP2C9, glutathione S-transferases (GST), UDP-glucuronyltransferases (UGT)
[13, 60, 61]. Unfortunately, most studies refer to the effects and
consequences of the extract and do not differentiate between the
different constituents. Whitten et al. [37] have examined 22 clinical
trials to analyze the effect of SJW extracts on the metabolism of
drugs by CYP3A. The authors found that all of the 19 studies that
used high-dose hyperforin extracts (>10mg=day) had outcomes
consistent with CYP3A induction, while the three studies using
low-dose hyperforin extracts (<4mg=day) demonstrated no significant effect on CYP3A. Studies in humans have demonstrated that
daily doses of Hypericum extract of 900 mg or higher determined a
greater effect on CYP3A4 induction than lower doses [13, 62].
Moreover studies in healthy volunteers suggest that a treatment
with Hypericum extract lasting more than 10 days is needed to observe a significant induction of CYP3A4 [63-65]. Clinically relevant drug interactions have been described for imatinib, irinotecan,
whereas in vitro data demonstrate the induction of docetaxel metabolism by hyperforin [13].
Imatinib is metabolized primarily by CYP3A4 with minor involvement of other pathways, including CYP1A2, CYP2D6 and
CYP2C9 [66]. Two trials performed in healthy volunteers have
shown decreased plasma concentrations of imatinib after administration of Hypericum extract [67-68]. In an open-label study in 13
healthy adult volunteers single 400-mg oral doses of imatinib were
administered before and after 2 weeks of treatment with SJW 300
mg 3 times/day [67]. Hypericum extract significantly altered the
pharmacokinetics of imatinib, with reduction of 32% in the area
under the plasma concentration-time curve (AUC), 29% in maximum observed concentration, and 21% in half-life. Similar results
were obtained by Frye et al. [68] in an open-label study in 12
healthy subjects, where a regular dose of 400 mg imatinib was administered orally on day 1 and day 15 and Hypericum extract was
given at a dose of 300 mg three times daily from day 4 to day 17.
The authors found that Hypericum extract administration increased
imatinib clearance by 43%, determining a reduction of 30% in the
AUC, whereas maximum observed concentration was lowered by

6 Current Drug Metabolism, 2011, Vol. 12, No. 5

20% and the half-life decreased by 12.8 hours to 9.0 hours [68].
Although no clinical studies have been conducted in chronic leukemia patients, it should be underscored the potential clinical significance of this drug interaction, according to the narrow therapeutic window of imatinib [67, 68], and also considering the
reduced response to imatinib observed in patients taking
phenytoin, another CYP3A4 inducer [69]. Clinicians should be
therefore aware of this potential drug interaction in order to
avoid the concomitant administration of imatinib and Hypericum
extract and finally to maintain clinical effectiveness of imatinib.
Irinotecan is an important anticancer drug in management of
advanced colon cancer that belongs to the group of topoisomerase-I
inhibitors. Irinotecan is a prodrug activated by liver carboxylesterases to the active metabolite SN-38. In addition, irinotecan is
also oxidized by CYP3A4 to the inactive metabolites [70]. Hu et al.
[71] have demonstrated that a long-term (14 days) pretreatment
with SJW in rats led to a significant decrease both in the initial
plasma concentration and in the AUC of irinotecan, also reducing
the maximum plasma concentration of SN-38. As observed in preclinical models Mathijssen et al. [72] found that concomitant use of
the Hypericum extract (900 mg/day) in five patients with cancer
treated with irinotecan, led to a significant 42% decrease in plasma
levels of SN-38, compared with irinotecan monotherapy. The
authors also observed that the degree of myelosuppression was substantially worse in the absence of SJW. This study suggest that irinotecan metabolism and toxicity are altered by Hypericum extract and that the two drugs cannot be given safely in combination without compromising overall anticancer activity.
Similar results can be expected with other anticancer drugs
that are at least partial substrates for CYP3A4, such as taxanes
(e.g docetaxel). Docetaxel is a taxane antineoplastic agent with a
broad spectrum of antitumor activity [73] and a mechanism of action that involves both an abnormal polymerization of tubulin and
the disruption of the mitotic spindle, which finally leads to an inhibition of cell division [74]. Primary human hepatocyte cultures
have been used to characterize the effect of hyperforin on docetaxel
metabolism [75]. In vitro concentrations of hyperforin, corresponding to clinically relevant concentration achieved by a
regular dosage of Hypericum extract of 900 mg/day, strongly
induced the metabolism of docetaxel (up to a 7-fold increase in
the degradation of docetaxel). Clinical studies are needed to confirm both the overall impact of hyperforin on docetaxel clearance
and the clinical relevance of this potential drug interaction, although it would be very difficult to design a such clinical study involving patients contemporary exposed both to Hypericum extract
and docetaxel. On the basis of preclinical evidence we suggest that
a pharmacokinetic drug interaction might arise when Hypericum
extract is combined with docetaxel. Clinicians should be aware of
this potential drug interaction and should take appropriate action to
educate patients receiving docetaxel.
CONCLUSIONS
Depressive disorders are common among people with cancer
and are associated with significant disability and reduced survival.
Antidepressants used for the treatment of depressive disorders are
susceptible to metabolically-based drug interactions with anticancer
drugs. This article represented a critical and updated review describing the clinically relevant metabolic drug interactions between
antidepressants and antineoplastic drugs, focusing in particular on
the published kinetic studies involving SSRIs and Hypericum extracts.
A clinically relevant interaction has been documented between
certain SSRIs and tamoxifen, a selective estrogen receptor modulator which is currently used for the treatment and prophylaxis of
breast cancer. Fluoxetine and paroxetine are potent inhibitors of
CYP2D6 and administration of these SSRIs can reduce the clinical
benefit of tamoxifen by decreasing the formation of active metabo-

Caraci et al.

lites of this drug. Pharmacoepidemiological studies have also

clearly shown that women with breast cancer, who received paroxetine in combination with tamoxifen, are at increased risk for
death from breast cancer. Based on this evidence, it has been recommended to avoid the use of paroxetine, fluoxetine and bupropion
in women taking tamoxifen for the treatment or prevention of recurrence of breast cancer [58].
Hypericum extracts, commonly used to treat mild to moderate
forms of depression, by inducing CYP3A4 and also increasing the
expression of P-gp, can reduce both the plasma concentrations and
the clinical efficacy of different anticancer drugs such as imatinib,
irinotecan and docetaxel.
It is fundamental for clinicians to be aware of these potential
drug interactions, in order to prevent unwanted toxicities or a reduced clinical efficacy of anticancer drugs, and finally to choose, in
the clinical practice, an antidepressant with a more favorable drug
interaction profile.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
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