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Tuesday, November 16, 2010

Herb–drug interactions: an overview of the clinical evidence

Herb–drug interactions: an overview of the
clinical evidence


Herbal medicines are mixtures of more than one active ingredient. The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Hence, the likelihood of herb–drug interactions is theoretically higher than drug–drug interactions, if only because synthetic drugs usually contain single chemical entities. Case reports and clinical studies have highlighted the existence of a number of clinically important interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. Through induction of Cytochrome P-450 enzymes and/or P-glycoprotein, some herbal products (e.g. St John’s wort) have been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives and digoxin. The majority of such interactions involve medicines that require regular monitoring of blood levels. To date there is less evidence relating to the pharmacodynamic interaction. However, for many of the interactions discussed here, the understanding of the mechanisms involved is incomplete. Taking herbal agents may represent a potential risk to patients under conventional pharmacotherapy.

KEY words
 Herbal drugs, drug–drug interactions, Cytochrome P-450, oral contraceptives, indinavir,


Due to the growing use of herbals and other dietary supplements healthcare providers and consumers need to know whether problems might arise from using these preparations in combination with conventional drugs. The use of herbal products has dramatically increased over the past decade, driving physicians to become educated in regards to potential herbal complications and drug interactions. From 1990 to 1997, the herbal product market increased by 48%, with 42% of the population using alternative treatments and spending an estimated $27 billion on them [1] Herbal products are widely available, relatively inexpensive, and often make alluring but unsubstantiated claims. Herbal medicine appeals to consumers who believe that natural herbal products are preferable to synthetic pharmaceuticals [2]. A relevant safety concern associated to the use of herbal medicines is the risk of interaction with prescription medications [3-7]. This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin or digoxin [8]. Recent examinations have indicated that as many as16% of prescription drug users consume herbal supplements . Exacerbating the problem, herbal remedies are often marketed on the Internet with misleading and unproved claims.
Despite repeated warnings, consumers continue to equate ‘‘natural’’ with safe. As use becomes more prevalent and reports of adverse effects continue mount, there is an increasing need for health care professionals to understand better the potential complications associated with these herbal remedies. There are numerous products currently on the market that have been associated with toxicity. The aim of this article is to highlight the clinical interactions between herbal remedies and prescribed drugs. Theoretical herb drug interactions, which are based on in vitro experiments, animal studies, speculative and/or empirical evidence can be found elsewhere[9].

The nature of herbaldrug interactions
Natural products, unlike conventional drugs, provide a complex mixture of bioactive entities, which may or may not provide therapeutic activity. Often a complete characterization of all the chemical constituents from a natural product is unknown.
Additionally, chemical makeup of a natural product may vary depending on the part of the plant processed (stems, leaves, roots), seasonality and growing conditions. Combination products composed of multiple natural products complicate matters further. Not only does the complex nature of natural products complicate the determination of drug–herbal interactions, but the manufacturing process contributes to the overall complexity as well. Because herbal products are not regulated by the FDA, as previously stated, there are no standards for herbal products. Indeed, some products have been found to be misidentified, substituted and/or adulterated with other natural products or unwanted substances. Testing of the quality of more than 1200 dietary supplement products by the independent laboratory found that 1 in 4 dietary supplement products lacked the labeled ingredients or had other serious problems such as unlisted ingredients or contaminants. This creates a problem when evaluating the validity of drug–herbal interactions [10].


Herbal medicines follow modern pharmacological principles. Hence, herb–drug interactions are based on the same pharmacokinetic and pharmacodynamic mechanisms as drug–drug interactions [11]. Pharmacokinetic interactions have been more extensively studied and in vitro and in vivo studies indicated that the altered drug concentrations by co-administered herbs may be attributable to the induction (or inhibition) of hepatic and intestinal drug-metabolizing enzymes [particularly Cytochrome P-450 (CYP)], and/or drug transporters such as P-glycoprotein [12-13]. The CYP is the most important phase I drug-metabolizing enzyme system, responsible for the metabolism of a variety of drugs. Many herbs (e.g. St John’s wort, echinacea, kava and garlic) and natural compounds isolated from herbs (e.g. flavonoids, coumarins, furanocoumarins, anthraquinones, caffeine and terpenes) have been identified as substrates, inhibitors and/or inducers of various CYP enzymes [14]. Specifically, clinical studies have shown that long-term (2 weeks) St John’s wort administration significantly induced intestinal and hepatic CYP3A4 and possibly other CYP enzymes involved in drugs metabolism [15-21]. Moreover, a clinical study performed on 12 healthy subjects showed that echinacea modulated the catalytic activity of CYP3A at hepatic and intestinal sites (induction of hepatic CYP3A4 and inhibition of intestinal CYP3A4). By contrast, a number of herbal medicines, including green tea ginkgo garlic  saw palmetto  and Siberian ginseng [22] did not affect CYP3A4 and CYP2D6 activities in normal volunteers. P-glycoprotein in the intestine, liver and kidney may play an important role in the absorption, distribution, or excretion of drugs. P-glycoprotein appears to limit the cellular transport from intestinal lumen into epithelial cells and also enhances the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space [23]. Like CYP, P-glycoprotein is vulnerable to inhibition, activation, or induction by herbs and herbal constituents. Curcumin, ginsenosides, piperine, sylimarin and catechins may affect P-glycoprotein-mediated drug transport [24]. St John’s wort induces the intestinal expression of P-glycoprotein both in isolated cells and in healthy volunteers. Hyperforin, a major ingredient of St John’s wort, binds to orphan pregnane X receptor  resulting in a series of intracellular events leading to the expression of CYP3A4 and P-glycoprotein. A few pharmacodynamic interactions have also been described. Pharmacodynamic interactions may be additive (or synergetic), whereby the herbal medicine potentiates the action of synthetic drugs (e.g. interaction between the anticoagulant warfarin with antiplatelet herbs), or antagonistic, whereby the herbal medicine reduces the efficacy of synthetic drugs (e.g. kava possesses dopaminergic antagonistic properties and hence might reduce the pharmacological activity of the anti-parkinson drug levodopa) [25].

Much of the available information about the interaction between herbal products and prescribed drugs is gleaned from case reports, although clinical studies are now also beginning to appear in the literature. The published case reports are often incomplete as they do not allow us to conclude that a causal relationship exists. Even documented case reports have to be interpreted with great caution, as causality is not usually established beyond reasonable doubt. According to the scoring system described by Fugh-Berman and Ernst [26], 68.5% of the cases reported were classified as ‘unevaluable’ (i.e. reports contained inadequate information to assess the likelihood of an interaction), 18.5% were classified as ‘possible’ (i.e. reports provided some evidence for an interaction, but there may be other causes of the event) and 13% as ‘well documented’ (reports appeared to provide reliable evidence for an interaction.

Herbal medicine involved in Drug interaction
Result of interaction
Possible mechanism
Source of evidence


Gum guar,
St John’s wort, wheat bran

Decreased plasma
digoxin concentration

Multiple mechanisms:
(i) gum guar delays gastric emptying and
hence may reduce digoxin absorption
(ii) St John’s wort induces
P-glycoprotein which is involved in digoxin
(iii) Fibres in bran may trap digoxin in the gut.

Clinical studies




Spontaneous hyphema

Additive effect on platelet aggregation (ginkgolides have antiplatelet activity)

A case report



Pectin or oat bran

Decreased absorption
of lovastatin

Pectins or bran fibres may bind or trap lovastatin in the gut.

A clinical study


St John’s wort

Decreased plasma
digoxin concentration

Simvastatin is a substrate of P-glycoprotein
and is metabolized by CYP enzymes.
Both CYP enzymes and P-glycoprotein are
induced by St John’s wort

A clinical study



St John’s wort

(i) Over-anticoagulation

(ii) decreased
anticoagulant effect

(i) Additive effect on coagulation (ginger
inhibits platelet aggregation)
(ii)Phenprocoum n is metabolised by cytochrome enzymes which are induced
by St John’s wort.

A case report

A clinical study



St John’s wort

Decreased bioavailability
of verapamil

Induction of intestinal CYP3A4 by
St John’s wort.

A clinical study




St John’s wort

St John’s wort

St John’s wort

Decreased plasma levels of alprazolam

Decreased plasma levels of amitriptyline

Alprazolam is a specific probe for CYP 3A4,
which is induced by St John’s wort.

Amitriptyline is a substrate of both CYP2C19
and P-glycoprotein which are induced by St John’s wort.

Synergistic effect on 5-HT receptors
Clinical studies

A clinical study

A case report



Based on current evidence from in vitro, in vivo and clinical studies, herbals and other dietary supplements interact with many drugs. Still, drug-herbal interactions are difficult to evaluate because of the lack of reliability of these products. The interactions often involve drug-metabolizing enzymes and drug transporter systems, although pharmacodynamic interactions can also be involved. Because the pharmacokinetic and pharmacodynamic characteristics of most herbal and other dietary supplements are not completely recognized, potential interactions are not often predictable. Potential interactions are more likely to occur with drugs with narrow therapeutic indexes. The evidence-based evaluation used in the study can be used to evaluate the reliability of case reports.


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