Herb-Drug Interactions: Natural coumarins

2011

Natural coumarins are widespread in herbal medicines and vegetables. There is a misconception that if a plant contains natural coumarins it will have anticoagulant properties, but very specific structural requirements are necessary for this – namely there must be a non-polar carbon substituent at the 3-position of 4-hydroxycoumarin. Moreover, at present, there are no established interactions between warfarin and herbal medicines that have been attributed to the natural coumarin content of the herb. Even in the classic case of haemorrhagic death of livestock that led to the discovery of dicoumarol, it was the action of the mould on the natural coumarin in the sweet clover (melilot) that led to the production of the anticoagulant, so consumption of a spoiled product would seem to be necessary for this specific interaction to occur. This suggests that the occurrence of natural coumarins in dietary supplements or herbal medicines should not trigger immediate concern as regards interactions with anticoagulants.

The information in this family monograph relates to the individual natural coumarins, and the reader is referred back to the herb (and vice versa) where appropriate. Note that, to avoid confusion with the synthetic anticoagulant coumarins, such as warfarin, the term ‘natural coumarins’ has been used to describe those that are of plant origin.

Types, sources and related compounds

Natural coumarins are aromatic lactones and phenylpropa-noids based on 1,2-benzopyrone (coumarin). They usually occur naturally bound to one or more sugar molecules as glycosides rather than as the free aglycone. There are three major classes of natural coumarins based on the structure of the aglycone:

• Hydroxycoumarins: such as umbelliferone, aesculetin (esculetin), herniarin, scopoletin and osthol occur in many plants. Some are further derivatised or prenylated, and coumarins in this class are generally harmless. However, some of the substituted 4-hydroxyderivatives have potent anticoagulant properties. The classic example that occurs naturally is dicoumarol (bishydroxycoumarin), which can occur in mouldy forage crops when coumarin itself is transformed into dicoumarol by microbial action. This compound has been used therapeutically as an anticoagulant, and is also the causative agent of haemorrhagic sweet clover disease (caused by ingestion of mouldy Melilotus officinalis) in cattle. See melilot. Note that the coumarin anticoagulants used clinically (acenocoumarol, phenprocoumon, warfarin) are all synthetic 4-hydroxycoumarins.

• Furanocoumarins (furocoumarins): have an additional furan ring attached, and this group can be further divided into linear compounds including psoralen, 5-methoxypsoralen (bergapten) and methoxsalen (xanthotoxin or 8-methoxypsoralen), and angular compounds such as angelicin (isopsoralen) and pimpinellin (5,6-dimethoxyangelicin). Some furanocoumarins may have additional prenyl substitution (e.g. bergamottin, alloimperatorin) and some occur as dimers, for example the paradisins, which are found in grapefruit juice. Others are more complex, such as the highly toxic aflatoxin Bl, which is produced by microbial contamination of food crops with Aspergillus niger. Furanocoumarins are commonly found in food items. They are mainly present in the two large plant families Rutaceae and Apiaceae, but occur in others. The Rutaceae family includes grapefruit, and prickly ash. The Apiaceae family includes aniseed, asafoetida, celery, Chinese angelica, carrot, parsnip, and many other herbs and spices. Note that the furanocoumarins are thought to be principally responsible for the main drug interactions of grapefruit juice.

• Pyranocoumarins: have a fused pyran ring attached, and can be divided into linear or angular.

There is also a minor class of coumarins, the 4-phenylcoumarins such as mammeisin, which can also be classified as neoflavonoids.

Isocoumarins (1,4-benzopyrones) are more commonly known as chromones; the most important of these is khellin, a compound found in Ammi visnaga which was the basis for the development of the anti-allergic drug cromoghcate and the class III antiarrhythmic amiodarone. Apart from khellin, which is a smooth muscle relaxant with bronchodilatory and vasodilatory effects, little is known of their activities or toxicities.

Coumarin (1,2-benzopyrone) itself was initially isolated from the tonka bean, and is found in other herbs such as melilot, and in many vegetables, fruits, and spices. It has a sweet scent, recognisable as the odour of new-mown hay.

Use and indications

Natural coumarins have a wide spectrum of activity ranging from the beneficial to the highly toxic. Generally, the furanocoumarins are more biologically active than the other types. Unlike the flavonoids, and isoflavones, it is not possible to generalise about their group actions, and this also applies to their toxic and drug interaction effects. In addition, coumarin supplements are not marketed or taken in the way that isoflavone or flavonoid (bioflavonoid) products are. Therefore only the most notable actions of the natural coumarin derivatives will be outlined here.

(a) Anticoagulant activity

The anticoagulant activity possessed by some natural coumarins is not universal and should not be attributed to all of them. In order to have anticoagulant activity, there must be a nonpolar carbon substituent at the 3-position of 4-hydroxycoumarin. The best known natural example is dicoumarol (bishydroxycoumarin), which is formed by the action of moulds on coumarin in sweet clover, see melilot. It functions as a vitamin K antagonist and has been used therapeutically as an anticoagulant, but the anticoagulant coumarins commonly used clinically are all fully synthetic compounds (e.g. acenocoumarol, phenprocoumon, warfarin).

(b) Photosensitisation and PUVA

Many furanocoumarins cause phototoxicity by sensitising the skin to UV light. This can cause hyperpigmentation of the skin, and extracts of plants containing these compounds have been used in traditional medicine to treat vitiligo. This property is also responsible for the allergenicity that is characteristic of some plants in the Apiaceae and Rutaceae families, particularly giant hogweed (Heracleum mantegazzianum) and rue (Ruta graveolens).

Photochemotherapy or PUVA (psoralen plus UVA) is a recognised conventional treatment for certain skin disorders such as cutaneous T-cell lymphoma, chronic graft-versus-host disease and psoriasis. UVA irradiation can help these conditions and the effect is enhanced by oral treatment with psoralen and other furanocoumarin derivatives (including methoxsalen), which cause photosensitisation. The doses of psoralens used for these treatments (up to 1.2mg/kg) are very unlikely to be achieved with herbs containing methoxsalen, and therefore interactions involving the oral psoralens are probably unlikely to occur with herbs containing these substances.

(c) Antioxidant effects

The phenolic structure of the natural coumarins means that most will have free radical scavenging and therefore antioxidant effects. Many natural coumarins are potent metal-chelating agents and powerful chain-breaking antioxidants. However, these properties have, as yet, only been studied experimentally.

(d) Anti-inflammatory activity

There is experimental evidence from in vitro and animal studies to suggest that various natural coumarins have anti-inflammatory activity. Esculetin, herniarin, scopoletin and scopolin have been used in Spanish traditional medicine against inflammation, and scopoletin has been shown to be pharmacologically active, as has esculin, extracted from the stem bark of Fraxinus ornus.

Coumarin itself is an anti-inflammatory agent. This has been demonstrated in animal studies where a coumarin-containing extract of Melilotus officinalis was found to have similar anti-inflammatory action to that of hydrocortisone.Coumarin has also been used in the treatment of lymph-oedema.

(e) Chemopreventive and cytotoxic effects

Experimental work has suggested that natural coumarins may prevent carcinogenesis, or have cytotoxic effects. Further work is required to confirm whether this is a potential therapeutic use of these substances.

(f) Miscellaneous effects

Insecticidal, antidiabetic, antifungal and larvicidal, activities have all been described for natural coumarin derivatives. It has also been suggested that some of the natural coumarins may be reverse transcriptase, protease or integrase inhibitors, and may warrant further investigation for possible use in the management of HIV infection.

Coumarin has also been used in perfumery, and as a flavour. However, it has been banned as a food additive in numerous countries, or limits have been set on its use, because it is moderately toxic to the liver and kidneys.

Pharmacokinetics

(a) Coumarin

Coumarin is completely absorbed after oral administration, and in humans subject to extensive first-pass hepatic metabolism, by the cytochrome P450 isoenzyme CYP2A6, to 7-hydroxycoumarin (umbelliferone), which is less toxic and also occurs widely in plants. However, in some people, coumarin is much more hepatotoxic than in others, and this is thought to be due to reduced metabolism of coumarin by CYP2A6, and greater dependence on metabolism by CYP3A4 to form the more toxic 3-hydroxycoumarin and intermediates.

(b) Bergamottin and related products

Bergamottin is metabolised in vivo to 6′,7′-dihydroxybergamottin. In a study in 12 healthy subjects given single 6-mg or 12-mg doses of bergamottin, 8 subjects had measurable levels of bergamottin and 3 had detectable levels of 6′ ,7 ‘-dihydroxybergamottin.

(c) Effect on cytochrome P450 isoenzymes

Furanocoumarins are now recognised as major cytochrome P450 enzyme inhibitors. They are mainly responsible for the complex drug interaction profile of grapefruit products, as shown by a study using furanocoumarin-free grapefruit juice (see Natural coumarins + Felodipine), although other constituents contribute to the effect (see pharmacokinetics, under grapefruit). The furanocoumarins, bergamottin, bergaptol, dihydroxybergamottin, geranylcou-marin and paradisin A, have been shown to have inhibitory effects on CYP3A4, CYP2D6 and CYP2C9 in vitro, and paradisin B has also been found to be a potent inhibitor of human CYP3A4. Methoxsalen and 5-methoxypsoralen (bergapten) are inhibitors of CYP1A2. In clinical pharmacokinetic drug interaction studies oral methoxsalen 1.2mg/kg has been shown to markedly inhibit CYP1A2 using caffeine and theophylline as probe substrates. In another study, oral methoxsalen slightly increased ciclosporin levels. It is very unlikely that these doses of methoxsalen would be achieved using herbs containing psoralens including methoxsalen. However, the findings are presented for information.

(d) Effect on P-glycoprotein

In vitro data suggest that some of the furanocoumarms present in grapefruit juice, such as 6′,7′-dihydroxybergamottin and 6′,7′-epoxybergamottin, are able to inhibit P-glycoprotein activity, raising the possibility of interactions between drugs that are substrates of this transporter protein and furanocoumarins, see talinolol. However, another in vitro study has suggested that 6′,7′-dihydroxybergamottin does not affect the function of P-glycoprotein.

Interactions overview

None of the individual natural coumarins is used as a dietary supplement or herbal medicine on its own, but rather as the herbs that contain it. Any interactions of the herbal medicines containing natural coumarins are covered under the specific herb.

Coumarin itself and the psoralens such as methoxsalen are used in conventional medicine. The doses used for these treatments are very unlikely to be achieved by taking herbal medicines containing these substances, and therefore the interactions of drugs such as methoxsalen are not covered here.

The drug interaction potential of some of the furanocoumarins is well established, and has been identified by investigating the mechanism of the interactions involving grapefruit juice.

This monograph does not contain any of the interactions of the synthetic 4-hydroxycoumarin derivatives that are used as anticoagulants, such as warfarin, because these are not natural coumarins.

Natural coumarins + Ciclosporin

A citrus soft drink containing furanocoumarins increased the bioavailability of ciclosporin in an isolated case.

Clinical evidence

A lung transplant recipient taking ciclosporin had large variations in his ciclosporin levels, which ranged between 319 and 761 nanograms/mL, on discharge from hospital, which were unexplained by changes in his current medication or ciclosporin dose changes. It was found that, on the days when the ciclosporin levels were increased, the patient had drunk a citrus soft drink (Sun Drop) at breakfast. These fluctuations resolved when he stopped drinking the soft drink. However, a subsequent pharmacokinetic study in 12 healthy subjects found that neither Sun Drop nor another citrus soft drink, Fresca, had any significant effects on the pharmacokinetics of a single 2.5-mg/kg dose of ciclosporin. Both Sun Drop and Fresca were tested, and found to contain the furanocoumarin bergamottin 0.078 and 6.5mg/L, respectively (note that grapefruit, which is known to interact with ciclosporin, contains about 5.6mg/L). The authors note that factors such as genetic and disease-related variability in ciclosporin metabolism, as well as changes in the bergamottin content between batches of the drinks, may account for the contrasting results.

Experimental evidence

No relevant data found.

Mechanism

The authors of the report of an interaction with a citrus soda drink confirmed with the manufacturers that it contained furanocoumarins, such as bergamottin, which are thought to inhibit the cytochrome P450 isoenzyme CYP3A4, which is the major isoenzyme involved in the metabolism of ciclosporin.

Importance and management

The isolated report of an interaction between a citrus soft drink (containing furanocoumarins) and ciclosporin was not confirmed by a subsequent single-dose pharmacokinetic study in healthy subjectsand therefore its significance is unclear. The case does highlight the influence that diet can have on ciclosporin levels and it should be borne in mind should any unexpected changes in ciclosporin levels occur.

Natural coumarins + Felodipine

Clinical studies demonstrate that bergamottin and other furanocoumarins may cause a clinically relevant increase in the levels of felodipine, but note that other active constituents also present in grapefruit juice may interact by additive or synergistic mechanisms.

Clinical evidence

In a single-dose study in healthy subjects, the maximum plasma level of felodipine was increased by 33%, 35% and 40% by bergamottin 2, 6 and 12 mg, respectively, and by 86% by grapefruit juice 250 mL containing about 1.7 mg of bergamottin. The AUC0_12 of felodipine was increased by 37% by bergamottin 12 mg, and by 48% by the grapefruit juice. There was, however, a wide variation between individuals. In another study, one-quarter strength lime juice, which contained the same concentration of bergamottin as grapefruit juice, had much less effect on the AUC of felodipine than grapefruit juice (20% increase versus 80% increase).

A further study in 18 healthy subjects found that furanocoumarin-free grapefruit juice had no consistent effect on the pharmacokinetics of felodipine relative to orange juice, with AUC changes ranging between a decrease of 46% and an increase of 44%. The median increase in the AUC of felodipine was 104% (range 6% to 230%) in those subjects given grapefruit juice with furanocoumarins present. Furanocoumarins identified in the grapefruit juice included 6’7′-dihydroxybergamottin, bergamottin, bergamottin-like substances and spiroesters.

A study in 12 healthy subjects, which investigated the effects of grapefruit juice and fractions of grapefruit juice on the pharmacokinetics of felodipine, found that 6’7′-dihydroxybergamottin was not one of the main active ingredients. The fraction with the greatest 6’7′-dihydroxybergamottin concentration caused a smaller increase in the AUC of felodipine than the fraction with one-third the amount of 6’7′-dihydroxybergamottin.

Experimental evidence

No relevant data found.

Mechanism

The furanocoumarins inhibit the activity of the cytochrome P450 isoenzyme CYP3A subfamily in the intestinal wall so that the first-pass metabolism of felodipine is reduced, thereby increasing its bioavailability and its effects. However, individually, bergamottin does not cause as great an effect as grapefruit juice. Similarly, 6’7′-dihydroxybergamottin is not as active as grapefruit juice.

Importance and management

These studies demonstrate that bergamottin and other furanocoumarins may cause a clinically relevant increase in the levels of felodipine, but that other active constituents are also present in grapefruit juice, which may interact by additive or synergistic mechanisms.

Note that the interaction of grapefruit juice and felodipine is established and the manufacturers of felodipine say that it should not be taken with grapefruit juice.

Because any interaction between furanocoumarins and felodipine appears to depend upon interactions between the individual furanocoumarin constituents present, it is difficult to predict what the effects of individual herbs may be. The effects of the individual furanocoumarins appear to be modest.

Natural coumarins + Food

No interactions found.

Natural coumarins + Herbal medicines

No interactions found.

Natural coumarins + Saquinavir

The interaction between natural coumarins and saquinavir is based on experimental evidence only.

Evidence, mechanism, importance and management

In an in vitro study in which human liver microsomes were incubated with bergamottin and with 6’7′-dihydroxybergamottin (furanocoumarins), the metabolism of saquinavir by the cytochrome P450 isoenzyme CYP3A4 was inhibited by both compounds to a similar extent to ketoconazole, a known CYP3A4 inhibitor. The transport of saquinavir by P-glycoprotein was also, to an extent, inhibited by 6’7′-dihydroxybergamottin.

Note that grapefruit juice, of which these furanocoumarins are a principal constituent, is known to modestly increase saquinavir levels.

It is difficult to extrapolate these findings to the clinical situation, but, if the effect of these furanocoumarins is similar to that of grapefruit juice, any interaction with herbal medicines containing these constituents would be expected to be mild, and of limited clinical relevance.

Natural coumarins + Statins

The interaction between natural coumarins and statins is based on experimental evidence only.

Evidence, mechanism, importance and management

An in vitro study demonstrated that bergamottin (a furanocoumarin) inhibited the metabolism of simvastatin in human and rat liver microsomes. Note that grapefruit juice, of which furanocoumarins such as bergamottin are a principal constituent, is known to markedly increase simvastatin levels, which may lead to myopathy and rhabdomyolysis, and avoidance of concurrent use is therefore advised. These experimental studies suggest that bergamottin plays a part in this interaction, and therefore, until more is known, a cautious approach would be to advise patients taking simvastatin (or lovastatin, which is similarly metabolised) to avoid taking supplements containing bergamottin, particularly in large quantities. If concurrent use is considered desirable, patients should be advised of the symptoms of myopathy (muscle pain, cramps, brown urine), and advised to promptly seek medical attention if they occur.

Natural coumarins + Talinolol

The interaction between natural coumarins and talinolol is based on experimental evidence only.

Evidence, mechanism, importance and management

In an in vitro study the effects of several furanocoumarins on P-glycoprotein were assessed using talinolol, a probe substrate for P-glycoprotein. Bergamottin did not affect the transport of talinolol, but 6’7′-dihydroxybergamottin and 6’7′-epoxybergamottin inhibited the P-glycoprotein transport of talinolol 5-fold and 2.5-fold, respectively, when used in similar concentrations to those found in grapefruit juice. Note that grapefruit juice, of which furanocoumarins are a principal constituent, has been shown to modestly decrease talinolol levels without altering its haemodynamic effects.

It is difficult to extrapolate these findings to the clinical situation, but, if the effect of these furanocoumarins is similar to that of grapefruit juice, any interaction with herbal medicines containing these constituents would be expected to be mild, and of limited clinical relevance.

Natural coumarins + Warfarin and related drugs

The interaction between natural coumarins and warfarin and related drugs is based on a prediction only.

Evidence, mechanism, importance and management

It has been suggested that herbal medicines containing naturally occurring coumarins might interact with warfarin and other anticoagulants by causing additive anticoagulant effects. On this basis, some authors have produced lists of plants that might increase the effect of warfarin solely because they contain natural coumarins.

It is known that, to have anticoagulant activity, a coumarin needs to be a 4-hydroxycoumarin with a nonpolar carbon substituent at the 3-position. Natural coumarins differ widely in their structures, as discussed under Types, sources and related compounds, and many do not meet this structural requirement. Moreover, even if anticoagulant activity for a natural coumarin was likely to be based on its structure, it would need to be determined whether it could occur in sufficiently high enough levels in a plant to be expected to be active. Also, it would need to be demonstrated that it is absorbed when given orally.

There are no established interactions between warfarin and herbal medicines that have been shown to be due to the natural coumarin content of the herb. Even in the classic case of haemorrhagic death of livestock after eating mouldy hay that led to the discovery of dicoumarol, it was the action of the mould on the natural coumarin in the sweet clover (melilot) that led to the production of the anticoagulant, so consumption of a spoiled product would seem to be necessary for this interaction to occur.

On this basis, the occurrence of natural coumarins in herbal medicines should not cause immediate concern.