Herb-Drug Interactions: Tea

2011

Contents

Camellia sinensis (L.) Kuntze (Theaceae)

Synonym(s) and related species

Camellia thea Link, Thea sinensis L.

Note that Green tea (predominantly produced in China and Japan) is produced from steam-treated tea leaves. Black tea or Red tea (predominantly produced in India, Sri Lanka and Kenya) is processed by fermentation and heating, whereas Oolong tea is partially fermented.

Pharmacopoeias

Powdered Decaffeinated Green Tea Extract (The United States Ph 32).

Constituents

Tea contains caffeine (around 1 to 5%), with minor amounts of other xanthines such as theophylline and theobromine. Tea also contains flavonoids, the content of which varies between green (unfermented) and black (fermented) tea. Green tea appears to contain greater quantities of the flavonol-type flavonoids than black tea. Black tea also contains theaflavins, which are produced during the fermentation process. Other flavonols present include quercetin and kaempferol. Oolong tea contains some unique flavones known as oolonghomobisflavins. Tea also contains up to 24% tannins.

Use and indications

The leaf buds and very young leaves of tea are used as a stimulant and diuretic, actions that can be attributed to the caffeine content. They are also used as an astringent for gastrointestinal disorders, which may be attributed to the polyphenols and tannins. Tea is very widely used to make a beverage. Green tea extracts, which are rich in polypheno-lics, are available as supplements. There is also a prescription-only ointment containing green tea extract (sinecatechins), which is used for the treatment of genital warts.

Pharmacokinetics

The pharmacokinetics of caffeine are discussed under caffeine. Black tea does not appear to affect the cytochrome P450 isoenzyme CYP2C9, as shown by the lack of effect on the pharmacokinetics of flurbiprofen. Similarly green tea catechins do not appear to affect the metabolism of caffeine, losartan, dextromethorphan, or alprazolam, suggesting a lack of effect on the isoenzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4, respectively.

For information on the pharmacokinetics of individual flavonoids present in tea, see flavonoids.

Interactions overview

Tea can contain significant amounts of caffeine, therefore the interactions of caffeine, are relevant to tea, unless the product is stated as decaffeinated. Black tea appears to reduce the absorption of iron, whereas green tea appears to have much smaller, if any, effects. Both black and green tea may cause a modest increase in blood pressure, which may be detrimental to the treatment of hypertension. Tea, particularly green tea catechins, may have some antiplatelet effects, which may be additive to those of conventional antiplatelet drugs. Case reports suggest that tea may reduce the INR in response to warfarin.

Green tea extracts do not appear to affect the pharmacokinetics of alprazolam, caffeine, ciclosporin, dextromethorphan, irinotecan and losartan, and have only modest effects on the pharmacokinetics of buspirone, but some of these data need confirming in patients. Black tea does not appear to have a clinically relevant effect on the pharmacokinetics of flurbiprofen.

Milk does not appear to affect the absorption of flavonoids or catechins from tea, suggesting that the addition of milk does not impair the antioxidant effects of tea.

For information on the interactions of individual flavonoids present in tea, see under flavonoids.

Tea + Alprazolam

Green tea extract does not affect the pharmacokinetics of alprazolam.

Clinical evidence

In a pharmacokinetic study, 10 healthy subjects were given a single 2-mg dose of alprazolam before and after Decaffeinated Super Green Tea Extract 2 capsules twice daily for 14 days. The green tea extract did not affect the pharmacokinetics of alprazolam.

Experimental evidence

Because of the quality of the clinical evidence available, experimental data have not been sought.

Mechanism

These studies provide evidence that green tea catechins, at similardoses to the amount provided by average green tea consumption, are unlikely to affect the metabolism of drugs by the cytochrome P450 isoenzyme CYP3A4.

Importance and management

The available data suggest that no clinically relevant pharmacokinetic interaction would be expected between green tea and alprazolam. Alprazolam is used as a probe drug for CYP3A4 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between green tea and other CYP3A4 substrates is unlikely.

For the possible pharmacodynamic interaction between caffeine (a constituent of tea) and benzodiazepines, see Caffeine + Benzodiazepines and related drugs. Tea can contain significant amounts of caffeine, and this interaction should be applied to tea, unless the product is stated to be decaffeinated.

Tea + Antihypertensives

Both black and green tea may cause a modest increase in blood pressure, which may be detrimental to the treatment of hypertension.

Clinical evidence

There is a possibility that the effect of tea on blood pressure might differ from that of pure caffeine. There are few data on the effect of tea on blood pressure in patients treated with antihypertensives. One study in stable hypertensive patients taking beta blockers, calcium-channel blockers, nitrates and ACE inhibitors reported that 450 ml of black tea (containing approximately 190 mg of caffeine) increased systolic blood pressure by 5 mmHg two hours after consumption. This effect was similar to the increase seen with a single dose of 200-mg of caffeine. Drinking 900 mL of black tea daily for 4 weeks had no significant effect on blood pressure. However, the acute effects of tea remained: systolic blood pressure was still increased by 5 mmHg two hours after the patients drank 450 mL of black tea.There are a number of short-term intervention studies on the effect of tea on blood pressure, mainly in healthy subjects or patients with untreated mild hypertension. In one meta-analysis of 5 randomised studies of the effect of tea consumption for at least 7 days (median 4 weeks) on blood pressure, tea consumption was associated with no change in blood pressure, when compared with the control group (although this group took caffeine in two of the studies). In one of the studies in this review, the acute increase in blood pressure seen with both green tea and black (fermented) tea 30 minutes after consumption was actually higher than that from an equivalent dose of caffeine. However, the increases seen in ambulatory blood pressure after 7 days of regular consumption of green or black tea were small and not different to that of caffeine. In another study by the same research group, the acute effects of black (fermented) tea on blood pressure were not apparent when the tea was taken with a meal (high fat).

The only long-term studies are of epidemiological type. In the Nurses Health prospective cohort study I, tea consumption was not associated with an increased risk of developing hypertension, whereas in the cohort study II, there was a slight trend for increased risk of hypertension with increased caffeinated tea intake. However, in a cohort study in Taiwan, the risk of developing hypertension was reduced by regular tea (green or oolong) consumption. Similarly, in a cross-sectional study, tea intake (mostly black (fermented) tea with added milk) was related to lower blood pressure in older women.

There appear to be very few data on the effect of supplements containing tea extracts on blood pressure. In one study, which compared the addition of green tea extract or placebo with a low-energy diet, the green tea extract had no additional benefit on blood pressure over that achieved by modest weight loss. In a single-dose study, a supplement containing black tea extract (polyphenols and caffeine), guarana extract (caffeine), ginger extract, dill weed extract, rutin and vitamin C (TeaLean), there was an average 3.7mmHg increase in systolic blood pressure in the 2hours after ingestion, but no increase in diastolic blood pressure.

Experimental evidence

Because of the extensive clinical evidence available, experimental data have not been sought.

Mechanism

Acute intake of caffeine raises blood pressure, but some tolerance to this effect might possibly develop with regular consumption. See also Caffeine + Antihypertensives. Polyphenolics in tea might improve endothelial function, and might therefore lower blood pressure.

Importance and management

The evidence presented here is conflicting, and it is not possible to be conclusive about the long-term effect of tea intake (green or black) on blood pressure. However, any adverse effect appears to be modest. On acute intake, both green and black (fermented) teas and some herbal supplements (particularly if they contain caffeine) might increase blood pressure, although, from the limited information above, these increases appear to be small and not necessarily sustained during long-term intake. Bear this in mind in patients with poorly controlled hypertension who frequently consume tea, particularly in large quantities. Further study on the effects of tea on antihypertensives is needed. However, note that similar effects are known to occur with caffeine alone, see Caffeine + Antihypertensives.

Tea + Antiplatelet drugs

Tea, particularly green tea catechins, may have some antiplatelet effects, which may be additive to those of conventional antiplatelet drugs.

Clinical evidence

(a) Pharmacodynamic effects

In studies in healthy medication-free subjects, neither acute. nor chronic tea consumption of black (fermented) tea (with or without added milk) affected platelet aggregation, whereas two studies did report a reduction in platelet activation with chronic tea intake.Another study, in 49 patients with known coronary artery disease taking aspirin 325 mg daily, found no evidence that acute or chronic ingestion of black (fermented) tea affected ADP-induced platelet aggregation. There appears to be just one clinical study of green tea, which did not find any significant effect on platelet aggregation.

(b) Pharmacokinetic effects

A study in 5 healthy subjects found that 200 mL of tea (at a temperature of 50°C) increased the rate of absorption of salicylate from a single 500-mg dose of aspirin, when compared with water, but the maximum concentration of salicylate was not significantly affected. The authors note that this result may have been influenced by the high temperature of the tea and an alkaline pH, both of which can increase the dissolution rate of aspirin. Note that caffeine is known to have a modest effect on the absorption of aspirin, see Caffeine + Aspirin or Diclofenac.

Experimental evidence

Green tea catechins have been reported to inhibit platelet aggregation in mice and in vitro, in a dose-dependent manner. Bleeding time was also prolonged in mice, but aPTT, prothrombin time and thrombin time were not affected by green tea catechins added to human plasma. This suggested an antiplatelet rather than an antithrombotic effect. Another animal study by the same research group found that oral green tea catechins 25 and 50mg/kg inhibited arachidonic acid-induced platelet aggregation and the production of thromboxane A2 and prostaglandin D2.

Mechanism

There is in vitro evidence that flavonoids, and flavanols and procyanidin oligomers in particular, inhibit platelet aggregation,and this has been suggested as a mechanism to explain why some epidemiological studies show that a diet high in these substances is associated with a reduced risk of cardiovascular disease (see also Flavonoids + Anticoagulant or Antiplatelet drugs).

Importance and management

In general the evidence appears to suggest that black (fermented) tea does not have a clinically relevant effect on platelet aggregation. However, experimental studies using green tea catechins have found an antiplatelet effect, and this effect may, in theory, be additive to those of conventional antiplatelet drugs. Concurrent use need not be avoided (indeed combinations of antiplatelet drugs are often prescribed together) but it may be prudent to be aware of the potential for increased bleeding if green tea extracts, particularly in high doses, are given with other antiplatelet drugs such as aspirin and clopidogrel. Patients should discuss any episode of prolonged bleeding with a healthcare professional. Modest consumption is unlikely to cause any problems.

Tea + Buspirone

Green tea catechins have only modest effects on the pharmaco-kinetics of buspirone.

Clinical evidence

In a study in 41 healthy subjects, green tea catechin extract 4 capsules daily for 4 weeks caused a minor 21% increase in the AUC of a single 10-mg dose of buspirone. The green tea catechin extract used in this study, Polyphenon E, contained 80 to 98% total catechins, of which 50 to 75% (200 mg) was epigallocatechin gallate. It was essentially decaffeinated (0.5% w/w caffeine).

Experimental evidence

Because of the quality of the clinical evidence available, experimental data have not been sought.

Mechanism

These studies provide evidence that green tea catechins (at higher doses than the amount provided by average green tea consumption) are unlikely to affect the metabolism of drugs principally metabolised via cytochrome P450 isoenzyme CYP3A4.

Importance and management

No clinically relevant pharmacokinetic interaction is expected between decaffeinated green tea and buspirone. However, there is a possible pharmacodynamic interaction between caffeine (a constituent of tea) and benzodiazepines, see Caffeine + Benzodia-zepines and related drugs. Tea can contain significant amounts of caffeine, and therefore this interaction is relevant to tea, unless the product is stated to be decaffeinated.

Tea + Caffeine

Green tea catechins do not appear to affect the pharmaco-kinetics of caffeine.

Clinical evidence

In a study in 41 healthy subjects, 4 capsules of a green tea catechin extract taken daily for 4 weeks had no effect on the metabolism of caffeine to paraxanthine after a single 100-mg dose of caffeine. The green tea catechin extract used in this study, Polyphenon E, contained 80 to 98% total catechins, of which 50 to 75% (200 mg) was epigallocatechin gallate per capsule. It was essentially decaffeinated (0.5% w/w caffeine).

Experimental evidence

Because of the quality of the clinical evidence available, experimental data have not been sought.

Mechanism

This study provides evidence that green tea catechins (at higherdoses than the amount provided by average green tea consumption) are unlikely to affect the metabolism of drugs principally metabolised by the cytochrome P450 isoenzyme CYP1A2.

Importance and management

No pharmacokinetic interaction is expected between decaffeinated green tea and caffeine or other CYP1A2 substrates.

Note that tea usually contains caffeine, and therefore the interactions of caffeine, (including caffeine found in other medicines, supplements or foods) are relevant. Excess caffeine consumption can cause adverse effects, including headache, jitteriness, restlessness and insomnia. Reduce caffeine intake if problems develop.

Tea + Ciclosporin or Tacrolimus

Green tea catechins do not appear to affect ciclosporin levels, and may protect against the adverse renal effects of ciclosporin and tacrolimus.

Evidence, mechanism, importance and management

In a study in rats, epigallocatechin gallate (a green tea catechin) had no significant effect on ciclosporin levels and also appeared to protect against ciclosporin-induced renal damage. In another animal study, pre-treatment with green tea polyphenolic extract, followed by the addition of ciclosporin or tacrolimus, blunted the decrease in glomerular filtration rates seen with these drugs. Similar findings were reported in another animal study with ciclosporin.

These findings in animals provide limited evidence that green tea supplements are unlikely to interact adversely with ciclosporin or tacrolimus, and might actually be beneficial. However, until clinical data are available, it would be unwise for transplant recipients taking these immunosuppressants to take tea supplements. Usual consumption of tea beverages does not appear to be a problem.

Tea + Dextromethorphan

Green tea catechins do not appear to affect the pharmacokinetics of dextromethorphan.

Clinical evidence

In a study in 32 healthy subjects, 4 capsules of a green tea catechin extract taken daily for 4 weeks had no effect on the metabolism of dextromethorphan to dextrorphan after a single 30-mg dose of dextromethorphan. The green tea catechin extract used in this study, Polyphenon E, contained 80 to 98% total catechins, of which 50 to 75% (200 mg per capsule) was epigallocatechin gallate. It was essentially decaffeinated (0.5% w/w caffeine). Similar findings (a lack of a pharmacokinetic interaction with dextromethorphan) were reported in another study in which 7 subjects received a single 30-mg dose of dextromethorphan before and after Decaffeinated Super Green Tea Extract 2 capsules twice daily for 14 days.

Experimental evidence

Because of the quality of the clinical evidence (controlled pharmacokinetic studies), experimental data have not been sought.

Mechanism

These studies provide evidence that green tea catechins (at similaror higher doses than the amount provided by average green tea consumption) are unlikely to affect the metabolism of dextromethorphan.

Importance and management

Evidence from two well-designed clinical studies suggests that green tea does not affect the pharmacokinetics of dextromethorphan. Dextromethorphan is used as a probe drug for CYP2D6 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between green tea and other CYP2D6 substrates is unlikely.

Tea + Flurbiprofen

Black tea does not appear to have a clinically relevant effect on the pharmacokinetics of flurbiprofen.

Clinical evidence

In a single-dose study in healthy subjects, brewed black tea (Lipton Brisk tea) had no effect on the clearance of elimination half-life of flurbiprofen.

Experimental evidence

An in vitro study reported that a sample containing brewed black tea 2.5% inhibited the hydroxylation of flurbiprofen by CYP2C9 by 89%.

Mechanism

These studies provide evidence that black (fermented) tea is unlikely to affect the metabolism of flurbiprofen.

Importance and management

Although experimental studies suggested that black tea may inhibit the metabolism of flurbiprofen, the study in healthy subjects suggests that any effect is not clinically relevant. No pharmacokinetic interaction is therefore expected between black (fermented) tea and flurbiprofen. Flurbiprofen can be used as a probe drug for CYP2C9 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between black tea and other CYP2C9 substrates is unlikely

Tea + Food

Milk does not appear to affect the absorption of flavonoids or catechins from tea, suggesting that the addition of milk does not impair the antioxidant effects of tea.

Clinical evidence

In a study in 12 healthy subjects, blood levels of catechins did not differ when black (fermented) tea was taken with the addition of milk (100 mL semi-skimmed plus water 500 mL with 3 g of instant tea) compared with no milk (3 g instant tea with water 600 mL). Similarly, in another study, plasma levels of the flavonoids quercetin and kaempferol did not differ when black (fermented) tea was drunk alone or with the addition of 15mL of milk to 135mL of tea.Another study showed similar findings (no difference in increase in total phenols, catechins, quercetin and kaempferol). Conversely, a slight 17% decrease in the AUC of catechins when black tea was taken with the addition of 70 mL milk was reported in another study. As regards the plasma antioxidant effect of tea, three studies- found that the addition of milk to black (fermented) tea did not alter the increase in antioxidant potential, whereas one study found that the addition of milk to black tea (3 measures consumed between 9 am and 12 noon) markedly reduced the increase in antioxidant effect at 12 noon, but it was only slightly reduced at 3 pm. The addition of milk also had no effect on the antioxidant effect of green tea in one study.

In another study in 16 healthy women, the addition of milk (to a final concentration of 10%) to black tea completely prevented the increase in endothelial-dependent flow-mediated dilation seen with black tea alone. However, the increase in endothelial-independent vasodilation was not affected by the addition of milk to tea.

Experimental evidence

Because of the extensive clinical evidence available, experimental data have not been sought.

Mechanism

It has been suggested that substances in milk (such as casein) might reduce the absorption of catechins and flavonoids from tea, but this has not been demonstrated in many of the studies.

Importance and management

Although the evidence is not entirely conclusive, there appears to be no important interaction between milk and black (fermented) tea, suggesting that the addition of milk does not reduce the antioxidant effects of tea. Similar levels of potentially active catechins and flavonoids can be expected, however the tea is taken. This suggests that milk is also unlikely to alter the absorption of catechins from green tea supplements.

Tea + Herbal medicines; Pepper

The interaction between green tea and pepper is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in mice, piperine modestly increased the bioavailability of epigallocatechin-3-gallate (EGCG) from green tea, with a 30% increase in the AUC1-5 and maximum plasma levels.

In vitro, piperine inhibited the intestinal glucuronidation of epigallocatechin-3-gallate by up to 60% when used at a concentration of 500 micromoles/L.

Mechanism

Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit.

Importance and management

The available evidence is from experimental studies only, but it does provide some evidence that piperine (an alkaloid derived from black pepper) can modestly increase bioavailability of the green tea catechin studied. However, the increases seen are probably unlikely to be clinically important, even if they were to be replicated in a clinical study. Evidence regarding the interactions of other herbal medicines with tea is limited, but the caffeine content of tea suggests that it may interact with other herbal medicines in the same way as caffeine, see Caffeine + Herbal medicines; Bitter orange, and Ephedra + Caffeine.

Tea + Irinotecan

The information regarding the use of green tea with irinotecan is based on experimental evidence only.

Evidence, mechanism, importance and management

Based on the results of in vitro studies, it was considered that usual pharmacological doses of green tea catechins were unlikely to inhibit the formation of active metabolites of irinotecan. There was no induction of CYP3A4 metabolism, and just modest and variable induction of glucuronidation (UGT1A1). However, the authors did conclude that these effects require confirmation in patients.

Tea + Iron compounds

Black tea appears to reduce the absorption of iron and may contribute to iron deficiency anaemia. Green tea appears to have much smaller, if any, effects.

Clinical evidence

(a) Black tea

There are few data on the effect of tea on the absorption of iron from supplements. One case report describes an impaired response to iron, given to correct iron deficiency anaemia, in a patient drinking 2 litres of black tea daily. The patient recovered when the black tea was stopped. This report did not specify whether the black tea was tea without milk, or black (fermented) tea.

Some short-term controlled studies show a marked reduction in the absorption of dietary non-haem iron with black (fermented) tea beverage, some of which are cited for information. In one of these, in a series of studies in healthy subjects, a 275 mL serving of black (fermented, Assam) tea reduced the absorption of radiolabelled iron from a 50 g bread roll by 79 to 94%. The tea was prepared by adding 300 mL of boiling water to 3 g of Assam tea, then infusing for 10 minutes before straining and serving. Milk added to the tea had very little effect on the reduction in iron absorption. A study found that 150 mL of black tea reduced the absorption of radiolabelled iron from a test meal by 59% in 10 women with iron deficiency anaemia and by 49% in 10 control subjects without anaemia. When the quantity of tea was increased to 300 mL iron absorption was reduced by about 66% in both groups.

Whether these reductions in iron absorption are important in the development of iron deficiency anaemia is less clear. Various epidemiological studies have looked at the correlation between tea consumption and iron deficiency in different populations. In one review of 16 of these studies, tea consumption did not influence iron status in people with adequate iron stores (as is common in the West), but there seemed to be a negative association between tea consumption and iron status in people with marginal iron status.Another report describes no change in the absorption of a single dose of iron (2 to 15.8mg/kg) in 10 iron-deficient children when the iron was given with 150 mL of tea (type unspecified) instead of water.

(b) Green tea

A study found that green tea extract (37 mg catechins) showed a modest 26% reduction in iron absorption, and another study, of pure epigallocatechin gallate 150mg and 300 mg, found only a 14% and 27% reduction in iron absorption, respectively. A study in 4 elderly patients with iron deficiency anaemia and 11 control patients found no evidence that green tea inhibited the absorption of iron from sodium ferrous citrate. Another study in pregnant women with iron deficiency anaemia reported a slightly higher resolution rate for anaemia in patients taking green tea.

Note that tea has been used with some success in reducing iron accumulation and the frequency of phlebotomy in patients with iron overload syndromes.

Experimental evidence

Because of the extensive clinical evidence available, experimental data have not been sought.

Mechanism

Tannins found in tea are thought to form insoluble complexes with non-haem iron and thus reduce its absorption. Other polyphenolic compounds found in tea may also reduce the bioavailability of non-haem iron. One study reported that beverages containing 100 to 400 g of polyphenols may reduce iron absorption by 60 to 90%.

Importance and management

The general importance of these findings is uncertain, but be aware that black tea consumption may contribute to iron deficiency anaemia. However, it has been suggested that no restrictions are required in healthy patients not at risk of iron deficiency. Conversely, the suggestion is that patients at risk of iron deficiency (which would include those requiring iron supplements) should be advised to avoid tea with meals and for one hour after eating. Note that tea is not generally considered to be a suitable drink for babies and children, because of its effects on iron absorption. Milk does not attenuate the effect of black (fermented) teas on iron absorption.

The available data suggest that green tea extracts rich in catechins have less effect on iron absorption than tea beverages from black (fermented) teas.

Tea + Losartan

Green tea extracts do not appear to affect the pharmacokinetics of losartan.

Clinical evidence

In a study in 42 healthy subjects, green tea extract four capsules daily for 4 weeks had no effect on the metabolism of a single 25-mg dose of losartan to the metabolite E3174. The green tea catechin extract used in this study, Polyphenon E, contained 80 to 98% total catechins, of which 50 to 75% (200 mg per capsule) was epigallocatechin gallate. It was essentially decaffeinated (0.5% w/w caffeine).

Experimental evidence

Because of the quality of the clinical evidence (controlled pharmacokinetic studies), experimental data have not been sought.

Mechanism

This study suggests that green tea catechins do not affect the metabolism of losartan.

Importance and management

Evidence is limited to this one study, which suggests that no pharmacokinetic interaction is expected between decaffeinated green tea extract and losartan. Losartan can be used as a probe drug for CYP2C9 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between green tea extracts and other CYP2C9 substrates is unlikely.

Tea + Warfarin and related drugs

Case reports suggest that tea may reduce the INR in response to warfarin.

Clinical evidence

A patient taking warfarin had a reduction in his INR from a range of 3.2 to 3.79 down to 1.37, which was attributed to the ingestion of very large quantities of green tea (about 2 to 4 litres each day for one week). This interaction was attributed to the vitamin K content of the tea. However, although dried tea, including green tea, is very high in vitamin K1, the brewed liquid made from the tea contains negligible amounts of vitamin K1; and is therefore not considered to contribute any vitamin K1 to the diet. The reason for this interaction is therefore unclear, unless the patient was eating some of the brewed tea leaves.

Another man stabilised on warfarin was found to have an INR of 4.43 at a routine clinic visit, which was increased from 3.07 six weeks previously. The patient had stopped taking a herbal product Nature’s Life Greens that month because he did not have enough money to buy it. He had been taking it for the past 7 years as a vitamin supplement because he had previously been instructed to limit his intake of green leafy vegetables. He was eventually restabilised on warfarin and the same nutritional product. The product label listed 25 vegetables without stating the amounts or concentrations, but at least 5 of the listed ingredients are known to contain high levels of vitamin K1 including parsley, green tea leaves, spinach, broccoli and cabbage. It is therefore likely that it contained sufficient vitamin to antagonise the effect of the warfarin so that when it was stopped the warfarin requirements fell and, without an appropriate adjustment in dose, this resulted in an increased INR.

Experimental evidence

Because of the extensive clinical evidence available, experimental data have not been sought.

Mechanism

Unknown. Green and black (fermented) tea do not alter the pharmacokinetics of some CYP2C9 substrates. See losartan, and flurbiprofen. Therefore it is unlikely that a pharmacokinetic interaction occurs with warfarin, which is principally metabolised by this isoenzyme.

Importance and management

Evidence for an interaction between tea and warfarin appears to be limited to two case reports. Vitamin K1 antagonises the effect of warfarin and similar anticoagulants, and this is present in high levels in green tea leaves. However, it is a fat-soluble vitamin, and is therefore not present in brewed tea or water extracts of green tea. In general, a reduction in warfarin effects via this mechanism would be unexpected with tea or tea supplements. Nevertheless, some consider that increased monitoring of INR is advisable when patients taking warfarin want to stop or start any herbal medicine or nutritional supplement. Because of the many other factors influencing anticoagulant control, it is not possible to reliably ascribe a change in INR specifically to a drug interaction in a single case report without other supporting evidence. It may be better to advise patients to discuss the use of any herbal products that they wish to try, and to increase monitoring if this is thought advisable. Cases of uneventful use should be reported, as they are as useful as possible cases of adverse effects.

However, note that it has been suggested that tea, particularly green tea, may have antiplatelet effects. See Tea + Antiplatelet drugs. There is a well-established small increased risk of bleeding when aspirin at antiplatelet doses is combined with the anticoagulant drug warfarin. Theoretically, very high intake of green tea catechins may be sufficient to increase the risk of bleeding with anticoagulant drugs; however, firm evidence for this is lacking. Modest consumption is unlikely to cause any problems.