Chun Guang Li*1 Phd
Liping Yang1 MPharm
Shu-Feng Zhou2 Phd
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,, 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 Ginseng (Panax species), danshen (Salvia miltiorrhiza) and 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) ( Reports can be made electronically at, 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, 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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