Chun Guang Li*
1 PhdLiping Yang
1 MPharmShu-Feng Zhou
1. The Chinese Medicine Research Group, division of Chinese Medicine, RMIT University, Melbourne, Australia2. division of Pharmacy, School of Life Sciences, Queensland University of Technology, Brisbane, Australia
A B S T R A C TThe popular use of herbal products in the general community raises concerns for potential herb–drug interactions. The risk of herb–drug interactions is increased if the herbal medicines are used concurrently with drugs which have a narrow therapeutic range, or are used in certain groups of patients, such as the elderly or those with impaired liver and renal functions. This short paper reviews some important concepts in herb–drug interactions and cases involving Chinese herbal medicines. It is important for Chinese medicine practitioners to understand, monitor and report potential herb–drug interactions.
K e y W o R d S herb–drug interactions, Chinese herbal medicine, efficacy, safety, adverse reactions, cytochrome P450.
report to the Parliamentary Secretary to the Minister for Health
Chinese herbal medicine, as one of the most developed
and Ageing of Australia, prepared by the expert Committee on
remedies in traditional Chinese medicine, has been widely
Complementary Medicines, has identified potential herb–drug
used by Chinese medicine practitioners for the treatment
interactions as an important area, and encourages more research
of a variety of acute and chronic diseases and conditions for
on the safety of herbal and other complementary therapies.2
thousands of years. Generally speaking, most Chinese herbal medicine practitioners are familiar with the concept of herb–
In this short paper, we have outlined some important aspects
herb interactions according to Chinese medicine theory,
of herb–drug interactions in the context of Chinese herbal
such as the synergistic/additive and/or antagonistic actions
medicines. It is important for Chinese herbal medicine
of some Chinese herbs under certain clinical conditions.
practitioners to understand these concepts in order to optimise
However, many practitioners are less familiar with herb–drug
clinical therapies and to avoid potential adverse reactions related
interactions, possibly due to a limited understanding of the
mechanisms underlying herb–drug interactions or difficulties in accessing existing data in this area.
The significant increase in the use of herbal medicines in the
Australian community also raises concerns of potential toxicity of herbal products, including Chinese herbal medicines.1
A herb–drug interaction is defined as any pharmacological
Such concerns are valid, considering some consumers or
modification caused by a herbal substance(s) to another
patients may take these products concomitantly with multiple
exogenous chemical (e.g. a prescription medication) in the
conventional drugs for various conditions (particularly for
diagnostic, therapeutic, or other action of a drug in or on
chronic diseases and conditions in the elderly). The recent
the body.3 This relates to so called drug–drug interactions
* Correspondent author; e-mail: [email protected]
Aust J Acupunct Chin Med 2007;2(1):17–24.
CG Li, LP Yang and SF Zhou
(interactions between drugs), herb–herb interactions
disclose the use of herbal products to their physicians,10 and
(interactions between herbs) or drug–food interactions
most physicians have relatively limited knowledge of various
(interactions between drugs and food). Broadly speaking,
herbal products, the risk of potential herb–drug interactions is
the herb–drug interaction is also a kind of drug interaction,
increased. Thus, there have been efforts for implementation of
considering that the action of a herbal substance is eventually
co-ordinated toxicity-monitoring systems by the World Health
caused by chemical ingredients which may be known or
organization (WHo) (e.g. WHo Collaborating Centre for
unknown. For example, St John’s Wort (Hypericum perforatum
International drug Monitoring, www.who-umc.org), and by
a commonly used antidepressant herb, has been reported to
various governments, including those of Australia, the United
cause significant changes in the action of cyclosporine A in
Kingdom, the United States, Singapore and China, aimed at
transplant patients (for references, see Table 1). It also decreased
improving monitoring and timely reporting of potential herb–
plasma concentrations of a range of drugs including digoxin,4
warfarin5 and theophylline.6 It should be pointed out that some herb–drug interactions may be beneficial, e.g. enhancing
the efficacy or reducing the adverse reactions of an anti-cancer agent. Recently, a randomised clinical trial has demonstrated
that Chinese herbal medicine reduces chemotherapy-induced nausea.7 However, many herb–drug interactions can also be
Herb–drug interactions can be caused by various factors. They
harmful, e.g. causing adverse reactions or therapeutic failure.
may result from chemical reactions between different ingredients, or from changes or modifications to specific biochemical
pathways involved in the metabolism or actions of related drugs
or herbs. For example, certain Chinese herbs may interfere with the body’s drug transporters and metabolism enzymes, resulting in changes of the metabolism and consequently the actions of
The main reason for concern is that herb–drug interactions
may potentially affect the clinical safety and efficacy of related drugs or herbs. Although many interactions between herbs and
Most herb–drug interactions are mediated by pharmacodynamic
drugs may be too minor (in terms of pharmacokinetic and/or
and/or pharmacokinetic mechanisms. Pharmacodynamic
pharmacodynamic changes) to have any clinical significance, in
interactions involve synergistic or antagonistic interactions
some cases, these interactions may alter the clinical outcomes or
on the same drug targets, e.g. receptors, which can often be
the safety of the treatment involved. The risk of harmful herb–
predicted and avoided. For example, Ma Huang (Ephedra
drug interactions is of particular concern to both consumers
species) contains ephedrine-like alkaloids which exhibit
and practitioners of herbal and conventional medicines. There
sympathomimetic activities. Thus, Ma Huang may interact
has been an increasing number of reports on harmful herb–
with other sympathomimetic agents, resulting in increased
drug interactions globally, partly due to the popularity of using
actions of monamine oxidase inhibitors and adrenergic agonists
herbal products in the general population.8
such as clonidine, and decreased actions of bethanidine and guanethidine.11 Pharmacokinetic interactions are much
It is important to note that the use of multiple medicines will
more difficult to anticipate, as they occur through multiple
significantly increase the risk of potential herb–drug interactions,
mechanisms, including alterations of the drug’s absorption,
especially in the elderly or certain groups of consumers, such
distribution, metabolism and excretion. Most reported
as cancer patients. The risk for drug interactions increases
herb–drug interactions are pharmacokinetic interactions. For
with the number of products consumed. For example, the
example, certain herbal ingredients may inhibit P-glycoprotein-
risk for potential interactions when consuming two products
mediated drug transport in the liver and intestinal tract,
is 6%; five products, 50%; the risk increases to 100% when
resulting in changes of absorptions and actions of drugs which
consuming eight or more products.9 The likelihood of herb–
drug interactions is therefore theoretically higher than drug–drug interactions since most synthetic drugs usually contain a
Cytochrome P450 (CyP450) enzymes are the most important
drug-metabolising enzymes in the body and are responsible for the metabolism of more than 50% of therapeutic drugs.14
It should be pointed out, however, that our understanding of the
Herb–drug interactions often occur when CyP450 enzymes
interactions between herbs and drugs is still limited. It is difficult
are affected. In humans, there are 57 CyP450 isoenzymes,
to characterise and identify definitely a herb–drug interaction
and these are grouped into different classes or families. The
based only on case reports or case series studies. Considering
nomenclature of CyP450s employs a three-tiered classification
a significant number of patients or herbal consumers fail to
based on the conventions of molecular biology, indicated by
CG Li, LP Yang and SF Zhou
an Arabic numeral (family), a capital letter (subfamily) and
interact with ibuprofen, trazodone, fluoxetine, buspirone and
another Arabic numeral (gene), e.g. CyP1A2.15 Most drug
phenytoin (Table 1). It is interesting to note that both warfarin
oxidations are catalysed primarily by six CyP450 enzymes
and cyclosporine are well-known subtracts of CyP2C9 and
(CyP1A2, 2C9, 2C19, 2d6, 2e1 and 3A4/5). Among these,
CyP3A4 respectively. St John’s Wort is a potent inducer of
CyP3A4 is responsible for metabolising more than 50% of
Another example is Gancao (licorice, Glycyrrhiza glabra
The actions of CyP450 may be changed by herbal ingredients
which was reported to increase the plasma concentrations
through two different mechanisms: induction and inhibition.
of prednisolone28,29 by inhibiting the metabolism of
The induction of CyP450 usually requires a longer period
prednisolone, and also potentiating the skin vasoconstrictive
of time (e.g. several days), which may lead to decreased drug
action of hydrocortisone.30 Thus, it may potentially modify the
plasma levels (through increased drug metabolism), and
pharmacological effects of prednisolone and hydrocortisone.
consequently reduced drug effects. Conversely, the inhibition of CyP450 is usually immediate and may lead to increased
drug plasma levels (through decreased drug metabolism), and thus increased drug effects, which may result in significant
adverse reactions or toxicities. Many clinical adverse events have been associated with CyP450 inhibitions.
Generally speaking, herb–drug interactions are difficult to predict as they depend on a number of factors, including the
In addition to P450s, there are also other drug metabolism
conditions of a patient, dose and time of administration of
enzymes and transport proteins which may be modulated
drugs and herbs, and quality of herbal substances. often the
by herbal substances, such as UdP-glucuronosyltransferase
individual differences may determine the consequences of a
(UGT) enzymes and breast-cancer resistance proteins.
Given the chemical complexity of herbal compositions, it may
be easier to predict the potential interactions based on the pharmacological properties of the drug or herb involved (e.g. if the drug or herb has similar or different pharmacodynamic
A number of herb–drug interactions have been identified in
actions, or acts as the substrate or inhibitor/inducer of certain
humans,12,16 as shown in Table 1. The reported drugs include
CyP450s or P-glycoprotein). Certain models have been
warfarin, aspirin, phenprocoumon, midazolam, alprazolam,
developed to predict potential herb–drug interactions, using
amitriptyline, oral contraceptives, indinavir, ritonavir,
saquinavir, digoxin, cyclosporine, tacrolimus, imatinib and irinotecan.12 There are also numerous studies on animals or
It is important to note that herb–drug interactions are likely
cells indicating potential herb–drug interactions, although the
to be under-reported. Currently, only a small number of
relevance of the evidence to humans has yet to be established.
drugs and herbs have been tested in clinical trials for potential interactions. Chinese medicine practitioners and physicians
one of the most commonly reported drugs involved in herb–
should examine prescribed drugs and herbal formulations/
drug interactions is warfarin. More than 15 different herbs
products to identify whether any ingredients of concern are
were reported to interfere with warfarin (and related drugs,
involved. They should also monitor clinical signs of the patients
such as heparin, aspirin, and coumarin derivatives). A number
for any changes in responses or side effects of administered
of Chinese herbs may potentially interact with warfarin, to
drugs after taking herbal medicines. The general advice is to
cause bleeding. Such herbs include Ginger (Zingiber officinale
avoid the concurrent use of drugs and herbal medicines in
species), danshen (Salvia miltiorrhiza
dang gui (Angelica sinensis
)17,18 (Table 1).
one of the most commonly reported herbs involved is St John’s Wort (Hypericum perforatum
), which has been reported
to interfere with cyclosporine, digoxin, theophylline, oral contraceptives, methadone, fluoxetine and buspirone (Table
In Australia, all suspected drug interactions, including suspected
1). For example, a number of cases have been reported
adverse reactions to prescription medicines, vaccines, over-the-
showing that St John’s Wort decreased cyclosporine blood
counter and complementary medicines, should be reported to
concentrations.19-27 Gingko biloba
was also reported to
the Adverse drug Reactions Unit at the Therapeutic Goods
CG Li, LP Yang and SF Zhou
TABLe 1 Reported Herb–Drug Interactions in Humans
St John’s Wort (Hypericum perforatum
Siberian ginseng (Eleutherococcus senticosis
devil’s claw (Harpagophytum procumbens
CG Li, LP Yang and SF Zhou
Notes: All clinical trials included in the table demonstrated significant herb–drug interactions, except the one marked with *, which showed no significant interaction between Warfarin and Ginkgo. ** Indicates that the Latin name was not given in the relevant study, meaning that the herb species could not be identified with certainty by the authors of this review.
Administration (TGA) (www.tga.gov.au/adr). Reports can be made electronically at www.tgasime.health.gov.au, or by using
Herb–drug interaction is an important issue affecting the
the ‘Blue Card’ pre-paid reporting form (available from www.
efficacy and safety of therapeutic treatments. Chinese herbal
tga.gov.au/adr), or by calling the Consumer Adverse Medication
medicine practitioners should have adequate knowledge in
events Line (telephone: 1300 134 237). The information to
this area and adopt proper strategies to monitor and report
be included in a report is the patient’s details, a description
potential herb–drug interactions in order to minimise harmful
of the suspected reaction and medicines involved, as well as
adverse reactions and improve the efficacy of Chinese herbal
any treatment and outcome details (refer to the Blue Card for
an information check-list). For complementary medicines, it will be useful to include product information such as AUST L number if possible.
CG Li, LP Yang and SF Zhou
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Elfo : Galadiir, Fenfaril, Lilliastre, Phirosalle, Enkirash, HalwyrOcchi tormentati, Occhi acuti o Occhi folli Umano : Avon, Morgan, Rath, Ysolde, Ovid, Vitus, Aldara, Xeno, UriCapelli acconciati, Capelli selvaggi, o Cappello a puntaVeste consumata, Veste al a moda, o Veste stravaganteCorpo grassoccio, Corpo raccapricciante, o Corpo esileAssegna questi punteggi alle tue capacità : 16 (+2),
REGLAMENTO Y NORMAS DE USO DE LA MEDIATEKA ARTÍCULO 1.- INTRODUCCIÓN El horario de apertura de las instalaciones de la Media-teka - a excepción de la sala de estudio y del espacio La Mediateka ocupa uno de los edificios de nueva plan-Medialab1, cuyos horarios se indican en los apartados ta del Centro de Ocio y Cultura AlhóndigaBilbao (en siguientes - será: adelante, el “Centro”