Herb-Drug Interactions: Resveratrol

Types, sources and related compounds

Resveratrol is a polyphenol present in most grape and wine products and is the compound largely credited with providing the health benefits of red wine. However, the concentration is very variable between foods and supplements, so it is difficult to evaluate the clinical relevance of the available information.

Use and indications

Resveratrol is used for its reputed anti-ageing effects. It is said to have antioxidant properties and antiplatelet effects, and is therefore promoted as having benefits in a variety of cardiovascular diseases, including atherosclerosis. It also has some oestrogenic and anti-inflammatory activity, and is under investigation in the prevention and treatment of cancer, because it appears to reduce cell proliferation.

Pharmacokinetics

An in vitro study reported that resveratrol inhibited the cytochrome P450 isoenzyme CYP3A4, but was much less potent than erythromycin, a known, clinically relevant, moderate CYP3A4 inhibitor. Similar results were found in other studies. Interestingly, red wine also inhibited CYP3A4, but this effect did not correlate with the resveratrol content.

In other studies resveratrol had only very weak inhibitory effects on CYP1A2, which are unlikely to be of any clinical relevance… Similarly, one study suggests that resveratrol and its primary metabolite do not inhibit CYP2C9 (see Resveratrol + Diclofenac) and CYP2D6, and resveratrol only weakly inhibits CYP2C19 (see Resveratrol + Mephenytoin).

Interactions overview

Resveratrol may have clinically significant antiplatelet effects which may be additive with antiplatelets and anticoagulant drugs as well as other drugs that may cause bleeding such as NSAIDs. An in vitro study reports that resveratrol had no significant effect on the metabolism of diclofenac and only weakly inhibited the metabolism of (S)-mephenytoin. Therefore clinically relevant pharmacokinetic interactions between resveratrol and substrates of CYP2C9 and CYP2C19, respectively, would not be expected. An in vitro study also found that resveratrol moderately inhibited the metabolism of paclitaxel; however, the clinical relevance of this is unclear.

Resveratrol + Anticoagulant or Antiplatelet drugs

The interaction between resveratrol and anticoagulants or antiplatelet drugs is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An ex vivo study using samples of platelet-rich plasma from 50 high-risk cardiac patients taking aspirin found that resveratrol significantly reduced platelet aggregation in response to collagen and adrenaline (epinephrine) in the samples taken from aspirin-resistant patients, but only had a minimal effect in those taken from aspirin-sensitive patients. Resveratrol had minimal effects on ADP-induced platelet aggregation in both groups of patients. Another in vitro study found that a low concentration of resveratrol (2 or 5 micromoles) increased the inhibitory effect of prostaglandins E1 and I2 on platelet aggregation in response to collagen, although it did not itself affect collagen-induced platelet aggregation. This subject has been extensively studied and is the subject of a number of review articles.

Mechanism

Resveratrol appears to enhance the inhibitory response to platelet aggregation. This effect may be additive to the effects of other drugs with antiplatelet effects.

Importance and management

Although there appears to be a plethora of in vitro studies to support the antiplatelet role of resveratrol, there is a lack of clinical data in humans. Therefore it is difficult to confirm if a clinically significant enhancement of antiplatelet effects would occur in patients taking resveratrol with 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 resveratrol is given with other antiplatelet drugs such as aspirin and clopidogrel. Patients should discuss any episode of prolonged bleeding with a healthcare professional.

Drugs that enhance antiplatelet effects may also increase the risk of bleeding in patients receiving anticoagulants such as warfarin. Clinically, the use of an antiplatelet drug with an anticoagulant should generally be avoided in the absence of a specific indication. However, if concurrent use is felt desirable it would seem sensible to warn patients to be alert for any signs of bruising or bleeding, and report these immediately, should they occur.

Resveratrol + Diclofenac

The information regarding the use of resveratrol with diclofenac is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An in vitro study using human liver micro somes found that resveratrol had no significant effect on the metabolism of diclofenac.

Mechanism

Nothing expected. Diclofenac can be used as a probe substrate for cytochrome P450 isoenzyme CYP2C9 activity.

Importance and management

Evidence is limited to this one in vitro study. Although there are no in vivo data available, it seems unlikely that resveratrol will affect the metabolism of diclofenac and therefore no dosage adjustments are likely to be needed if they are given together. Note that resveratrol may have some antiplatelet effects, which may be additive with those of NSAIDs such as diclofenac, consider also Resveratrol + Anticoagulant or Antiplatelet drugs, above. Diclofenac can be used as a probe drug for CYP2C9 activity, and therefore these results also suggest that a pharmacokinetic interaction between resveratrol and other CYP2C9 substrates is unlikely.

Resveratrol + Food

No interactions found.

Resveratrol + Herbal medicines

No interactions found.

Resveratrol + Mephenytoin

The information regarding the use of resveratrol with mephenytoin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An in vitro study using human liver micro somes found that resveratrol only weakly inhibited the metabolism of (S)-mephenytoin.

Mechanism

Nothing expected. Mephenytoin can be used as a probe substrate for cytochrome P450 isoenzyme CYP2C19 activity.

Importance and management

Evidence is limited to this one in vitro study. Although there are no in vivo data available, it seems unlikely that resveratrol will affect the metabolism of mephenytoin and therefore no dosage adjustments are likely to be needed if they are given together. Mephenytoin can be used as a probe drug for CYP2C19 activity, and therefore these results also suggest that a pharmacokinetic interaction between resveratrol and other CYP2C19 substrates is unlikely.

Resveratrol + Paclitaxel

The interaction between resveratrol and paclitaxel is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An in vitro study in human liver microsomes investigated the effects of resveratrol on the metabolism of paclitaxel. In both rat and human liver microsomes, resveratrol moderately inhibited paclitaxel metabolism.

Mechanism

Paclitaxel is metabolised by the cytochrome P450 isoenzyme CYP2C8 and, to a lesser extent, CYP3A4. In this study resveratrol appeared to moderately inhibit these isoenzymes.

Importance and management

The clinical relevance of this study is unknown. Further study is needed to confirm if this inhibition produces a clinically relevant increase in paclitaxel levels, which could also potentially increase the adverse effects of paclitaxel. However, the authors also suggested that, as the metabolites of paclitaxel are less active than paclitaxel itself, inhibiting its metabolism may be beneficial. There is currently insufficient evidence on which to base any clinical recommendations.