Herb-Drug Interactions: Flavonoids

2011

Contents

Bioflavonoids

The flavonoids are a large complex group of related compounds, which are widely available in the form of dietary supplements, as well as in the herbs or foods that they are originally derived from. They are the subject of intensive investigations and new information is constantly being published.

You may have come to this monograph via a herb that contains flavonoids. Note that the information in this general monograph relates to the individual flavonoids, and the reader is referred back to the herb (and vice versa) where appropriate. It is very difficult to confidently predict whether a herb that contains one of the flavonoids mentioned will interact in the same way. The levels of the flavonoid in the particular herb can vary a great deal between specimens, related species, extracts and brands, and it is important to take this into account when viewing the interactions described below.

Types, sources and related compounds

Flavonoids are a very large family of polyphenolic compounds synthesised by plants that are common and widely distributed. With the exception of the flavanols (e.g. catechins) and their polymers, the proanthocyanidins, they usually occur naturally bound to one or more sugar molecules (flavonoid glycosides) rather than as the free aglycones. The sub-groups of flavonoids, their main representatives, and their principal sources are as follows:

• Flavones: e.g. apigenin, luteolin; found in celery, and parsley. The rind of citrus fruits is rich in the polymethoxylated flavones, tangeretin (from tangerine), nobiletin and sinensetin.

• Flavonols: e.g. quercetin, kaempferol, myricetin, isorhamnetin; widely distributed in berries, teas, broccoli, apples and onions. Rutin (sophorin), also known as quercetin-3-rutinoside, is a common glycoside of quercetin; other glycosides include quercitrin, baicalin and hyperin. Morin is a flavonol found in Morus species.

• Flavanones: e.g. hesperetin (from oranges), naringenin (from grapefruit), eriodictyol (from lemons); and their glycosides, hesperidin, naringin and eriocitrin. They are most concentrated in the membranes separating the fruit segments and the white spongy part of the peel. Flavanone glycosides are often present in supplements as citrus bioflavonoids.

• Flavanols (Flavan-3-ols): monomers, e.g. catechins and gallic acid esters of catechins, epicatechins and gallic acid esters of epicatechins; found in teas, (particularly green and white), cocoa, grapes, berries, and apples. Dimers, e.g. theaflavins and gallic acid esters of theaflavins, and thearubigins also found in teas (particularly black and oolong). Proanthocyanidins are polymers of flavanols, also known as condensed tannins, the most frequent being procyanidins (polymers of catechin and epicatechin). Found widely in cocoa, some berries and nuts, hops and grapeseed.

• Anthocyanins: e.g. cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin; found widely in chocolate, apples, red, blue and purple berries, red and purple grapes, and red wine.

Isoflavones (Isoflavonoids): are a distinct group of flavonoids with phytoestrogenic effects and are considered elsewhere, see isoflavones.

Use and indications

Some prospective cohort studies show that a high dietary intake of flavonoid-rich foods is associated with a reduced risk of coronary heart disease, but they do not all show this effect. Other cohort and case — control studies show a reduced risk of some cancers. However, there do not appear to be any studies to show whether isolated flavonoid supplements confer similar benefits to flavonoid-rich foods. Many beneficial properties have been identified for flavonoids, one of the most popularly cited being their antioxidant activity. Other actions that are proposed to contribute to their biological effects include chelating metal ions, stimulating phase II detoxifying enzyme activity, inhibiting proliferation and inducing apoptosis, reducing inflammation, decreasing vascular cell adhesion molecule expression, increasing endothelial nitric oxide synthase (eNOS) activity and inhibiting platelet aggregation.

Pharmacokinetics

The bioavailability of flavonoids is relatively low due to limited absorption and rapid elimination, and they are generally rapidly and extensively metabolised. Flavonoid esters, glycosides or polymers require hydrolysis to the free aglycone before absorption, and this occurs by intestinal enzymes (e.g. beta-glucosidases) and colonic bacteria. During absorption, the aglycone is then conjugated by sulfation, glucuronidation or methylation. These conjugates are excreted back into the intestine by efflux pumps. Those absorbed are eventually excreted in the urine and bile, and may undergo enterohepatic recycling. It appears that metabolism of flavonoids by cytochrome P450 isoenzymes is probably minor compared with conjugation reactions for flavonoids.

The potential for flavonoids to alter drug metabolism by cytochrome P450 isoenzymes, in particular, and also intestinal and hepatic drug transporters, such as P-glycoprotein, has been extensively investigated in vitro. There are also some animal studies, but few human clinical pharmacokinetic studies, and those that are available have generally used very high doses of the flavonoids.

There is at present no reason to avoid flavonoids in the diet, or in the form of herbal medicines (most of which contain significant amounts of flavonoids naturally), and many positive reasons for including them. However, very high doses (such as the use of specific flavonoid supplements) could potentially alter the metabolism of other drugs that are substrates for CYP3A4 and/or P-glycoprotein, and increase the bioavailability of some drugs; for instance the statins, such as lovastatin and simvastatin; ciclosporin; benzodiazepines, such as midazolam; and digoxin.

Interactions overview

The interactions covered in this monograph relate to individual flavonoids. It may be possible to directly extrapolate some of these interactions to some flavonoid supplements, especially those regarding quercetin; however, caution must be taken when applying these interactions to herbs or foods known to contain the flavonoid in question. This is because the amount of the flavonoid found in the herb or food must be considered (this can be highly variable, and might not be known) and the other constituents present in the herb or food might affect the bioavailability or activity of the flavonoid (information that is usually unknown). Therefore, although data on isolated flavonoids are useful, it is no substitute for direct studies of the herb, food or dietary supplement in question.

Flavonoids + Aciclovir

The interaction between quercetin and aciclovir is based on experimental evidence only.

Evidence, mechanism, importance and management

Findings from an in vitro study suggest that quercetin might modestly increase the absorption of oral aciclovir by inhibiting intestinal P-glycoprotein. The effect of high-dose quercetin (80mg/L) was equivalent to that of verapamil 10 mg/L, which is an established, clinically relevant inhibitor of P-glycoprotein. However, because aciclovir has a wide therapeutic index, even if this change is seen in practice, it is unlikely to be clinically important.

Flavonoids + Antibacterials

The interaction between flavonoids and antibacterials is based on experimental evidence only.

Evidence, mechanism, importance and management

(a) Aminoglycosides

In a study, rats were given either the aglycone baicalein or the parent flavone baicalin orally. The bioavailability of baicalein from the parent flavone was reduced from 28% to about 8% in rats given neomycin and streptomycin, when compared with rats not given these antibacterials, but the antibacterials did not affect the bioavailability of administered baicalein.

These antibacterials decimate colonic bacteria, which are involved in the hydrolysis of baicalin to baicalein. This study used the combination of neomycin and streptomycin because previous research had shown that this combination was most effective in reducing intestinal microflora, and that a single aminoglycoside did not have this effect.

These findings are likely to have little clinical relevance, because individuals are rarely given combinations of aminoglycosides with such potent effects on colonic microflora. It would be of use to know the effect of standard broad-spectrum antibacterials in general clinical use. However, even these are only given for short courses, so any reduction in the effect of the flavonoid would be short-lived.

(b) Nitrofurantoin

In a study in rats, oral administration of high-dose chrysin 200 mg/ kg increased the AUC of nitrofurantoin by about 76% and decreased its clearance by 42%, whereas low-dose chrysin 50 mg/kg had no effect on the pharmacokinetics of nitrofurantoin.

Available evidence suggests that chrysin increases the AUC of nitrofurantoin by inhibition of the transporter protein BCRP.

The doses used in this study were much greater than those likely to be encountered clinically, and therefore these data suggest that even high doses of chrysin used as dietary supplements (e.g. 3 g daily) are unlikely to have a clinically important effect on nitrofurantoin pharmacokinetics.

Flavonoids + Anticoagulant or Antiplatelet drugs

The interaction between flavonoids and anticoagulant or antiplatelet drugs is based on a prediction only.

Clinical evidence

There are few clinical studies investigating whether the in vitro antiplatelet effect of flavonoids occurs in humans, and whether this effect could be clinically relevant, and findings are not consistent. Some studies are cited in the following section as examples to illustrate the differences.

Antiplatelet effects

In one randomised controlled study, a cocoa supplement (234 mg of cocoa flavanols and procyanidins daily) given for 28 days decreased collagen- and ATP-induced platelet aggregation when compared with placebo. Similarly, onion soup high in quercetin (one ‘dose’ of about 69 mg) inhibited collagen-stimulated platelet aggregation. However, in another study, neither dietary supplementation with onions 220 g daily (providing quercetin 114mg daily) nor supplementation with parsley 4.9 g daily (providing apigenin 84 mg daily) for 7 days affected platelet aggregation or other haemostatic variables. Similarly, a supplement containing quercetin 1 g daily and other flavonoids did not affect platelet aggregation in a placebo-controlled study in healthy subjects.

In a single-dose study in healthy subjects, a flavanol-rich cocoa beverage (897 mg total flavonoids in 300 mL) had a similar, but less marked, effect than aspirin 81 mg on adrenaline-stimulated platelet activation and function. The effect of the cocoa beverage and aspirin appeared to be additive.

Experimental evidence

Numerous in vitro studies show that many 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 flavonoids is associated with a reduced risk of cardiovascular disease.

Mechanism

Flavonoids might have antiplatelet effects, which, if confirmed, could be additive with other antiplatelet drugs. In addition, they might increase the risk of bleeding when used with anticoagulants.

Importance and management

There is a large amount of information regarding an interaction between flavonoids and antiplatelet drugs, but an interaction is not established. 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 intakes of flavonoids (e.g. from supplements) might have similar clinically important antiplatelet effects, and could therefore increase the risk of bleeding when taken with any anticoagulant drug, and have additive effects with antiplatelet drugs. However, available evidence is conflicting, with some studies showing that a number of flavonoids have antiplatelet effects and others finding no antiplatelet effects. Until more is known, some caution might be appropriate with high doses of flavonoid supplements. In practice this would mean being aware of an increased risk of bleeding, and patients being alert for symptoms of bleeding, such as petechiae and bruising. Modest doses of flavonoids are unlikely to cause any problems.

Flavonoids + Benzodiazepines

In a study, tangerine juice, containing tangeretin, did not affect the pharmacokinetics of midazolam. However, grapefruit juice, which contains different flavonoids, does increase levels of some benzodiazepines.

Clinical evidence

In a crossover study in 8 healthy subjects, tangerine juice (which contains the flavone tangeretin) 100 mL, given 15 minutes before and with a single 15-mg dose of oral midazolam, had no effect on the AUC and elimination of midazolam. The only change was a slight delay in midazolam absorption.

Note that grapefruit juice (a rich source of flavonoids) has a well-established inhibitory effect on the metabolism of some benzodiazepines, resulting in increased exposure (1.5- to 3.5-fold increase in AUC).

Experimental evidence

(a) Anxiolytic effect

In various animal models, the anxiolytic effects were additive for diazepam and baicalin, and synergistic for diazepam and hesperidin.

(b) Pharmacokinetics

In vitro, tangeretin (a flavone from tangerine) stimulated the hydroxylation of midazolam in human liver microsomes. Conversely, in another study, quercetin was found to be an inhibitor of the metabolism of midazolam, with kaempferol and naringenin also having some effect.

Mechanism

Theoretically, flavonoids might inhibit the metabolism of some benzodiazepines by the cytochrome P450 isoenzyme CYP3A4 (note that not all benzodiazepines are metabolised by this route). Some flavonoids have anxiolytic properties in animal models.

Importance and management

Contrary to what was predicted from in vitro studies using tangeretin, a single dose of tangerine juice did not appear to alter the pharmacokinetics of midazolam. In contrast, grapefruit juice, which contains different flavonoids, does increase levels of some benzodiazepines. However, grapefruit juice also affects the levels of some calcium-channel blockers, but studies with the flavonoid naringin have found no interaction, suggesting that naringin is not the primary active constituent of grapefruit juice (see calcium-channel blockers, below). Therefore individual flavonoids might not be anticipated to increase benzodiazepme levels. Furthermore, although evidence is preliminary, it is possible that high doses of some individual flavonoids such as hesperidin and baicalin might have additive anxiolytic effects with benzodiazepines, suggesting a possible pharmacodynamic interaction.

Flavonoids + Caffeine

Naringin does not appear to affect the pharmacokinetics of caffeine.

Clinical evidence

In a crossover study in 10 healthy subjects, changes in caffeine pharmacokinetics and physiological responses (resting energy expenditure, oxygen consumption and respiratory exchange ratio) were measured after an acute dose of caffeine 200 mg with or without naringin 100 or 200 mg. Naringin did not alter either the pharmacokinetics of caffeine or the physiological responses to caffeine. Note that grapefruit juice (which is a rich source of flavonoids) either does not interact with caffeine or causes only clinically irrelevant increases in caffeine levels.

Experimental evidence

In contrast to the clinical findings, in vitro evidence suggests that grapefruit juice and naringenin inhibit CYP1A2 activity in human liver microsomes. Nevertheless, it is not unusual for in vitro effects to be less marked or not apparent when studied in humans.

Mechanism

Although in vitro studies have suggested that grapefruit juice and one of its constituents, naringenin, may inhibit the metabolism of caffeine by the cytochrome P450 isoenzyme CYP1A2, this does not appear to occur in humans.

Importance and management

Although some of the data are conflicting, the balance of evidence suggests that flavonoids such as naringin would not be expected to alter the effects of caffeine or other substrates of CYP1A2 by a pharmacokinetic mechanism.

Flavonoids + Calcium-channel blockers

Supplements of specific citrus bioflavonoids do not appear to affect the pharmacokinetics of calcium-channel blockers to a clinically relevant extent.

Clinical evidence

(a) Felodipine

In a crossover study in 9 healthy subjects, 200 mL of an aqueous solution of naringin 450 micrograms/mL had no effect on the mean AUC of a single 5-mg dose of felodipine. This contrasted with the effect of 200 mL of grapefruit juice (determined to have the same naringin level), which doubled the AUC of felodipine. In another study, in 12 healthy subjects, the liquid fraction (after centrifugation and filtration) of grapefruit juice, which contained naringin 148 mg, had less effect on the AUC of felodipine than the particulate fraction (the sediment after centrifugation, which contained 7mg of naringin; 20-fold less). The AUC of felodipine increased by about 50% with the liquid fraction and by about 100% with the particulate fraction.

(b) Nifedipine

In a crossover study in 8 healthy subjects, high-dose quercetin 200 mg given the night before, 100 mg given on waking and 100 mg given with nifedipine 10 mg had no effect on the AUC of nifedipine. This contrasted with the effect of 200 mL of double-strength grapefruit juice (a rich source of flavonoids), which increased the AUC of nifedipine by about 50%.

(c) Nisoldipine

In a crossover study in 12 healthy subjects, the AUC of a single 20-mg dose of nisoldipine was not altered by naringin 185 mg (given simultaneously), but was increased by 75% by 250 mL of grapefruit juice (a rich source of flavonoids).

Experimental evidence

One research group has extensively investigated the effects of various flavonoids on the pharmacokinetics of various oral calcium-channel blockers in rats and rabbits. In these studies, the flavonoids tested (morin, naringin, quercetin) caused dose-dependent increases in the AUC of diltiazem (30 to 120%), nimodipine (47 to 77%) and verapamil (27 to 72%). No effect was seen on the elimination half-life. An interaction occurred when the flavonoid was given 30 minutes before the calcium-channel blocker, but not when it was given simultaneously.

Mechanism

The increased bioavailability of calcium-channel blockers in animals pretreated with morin, naringin or quercetin may result from inhibition of P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4. However, no individual flavonoids have had any effect on the bioavailability of calcium-channel blockers in humans. It is probable that furanocoumarins are more important for the grapefruit interaction in humans, see also Natural coumarins + Felodipine.

Importance and management

Experimental evidence for an interaction is extensive, but less is known about any interaction between flavonoids and calcium-channel blockers in humans. In contrast to the effect of grapefruit juice, no individual flavonoid has had any effect on the pharmacokinetics of a calcium-channel blocker in clinical studies (naringin with felodipine, quercetin with nifedipine, naringin with nisoldipine). Although, high doses of these flavonoids have increased levels of several calcium-channel blockers in animals, the clinical data seem to suggest that this is not applicable to humans. Supplements of specific citrus bioflavonoids are therefore unlikely to interact with calcium-channel blockers; however, an interaction might occur with extracts of grapefruit if these contain constituents other than just the flavonoids (e.g. furanocoumarins such as bergamottin). Consider also Grapefruit + Calcium-channel blockers.

Flavonoids + Ciclosporin

A study found that quercetin increased the bioavailability of ciclosporin.

Clinical evidence

In a study in 8 healthy subjects, a single 300-mg dose of ciclosporin was given four times: alone, with oral quercetin 5 mg/kg, 30 minutes after oral quercetin 5 mg/kg or after a 3-day course of quercetin 5 mg/kg twice daily. It was found that the AUC of ciclosporin was increased by 16% when given with a single dose of quercetin, by 36% when given after single-dose quercetin and by 46% when given after multiple-dose quercetin.

Experimental evidence

(a) Nephrotoxicity

There are some data suggesting that flavonoids might reduce the renal toxicity of ciclosporin. For example, in one study in rats, quercetin given with ciclosporin for 21 days attenuated the renal impairment and morphological changes (such as interstitial fibrosis), when compared with ciclosporin alone.

(b) Pharmacokinetics

In contrast to the clinical evidence above, in an animal study, giving single doses of oral ciclosporin with quercetin 50 mg/kg resulted in a 43% and 42% decrease in the AUC of ciclosporin in rats said pigs, respectively (note, this did not reach statistical significance mpigs).In a further study in rats, onion (which is a rich source of quercetin) caused a 68% reduction in the levels of ciclosporin given orally, but had no effect on the AUC of ciclosporin given intravenously.

Similarly, in another study, morin decreased levels of ciclosporin in blood by a modest 33%, and also decreased levels in other tissues (by 17% to 45%). However, despite this reduction, the ciclosporin-suppressed Thl immune response was not reduced by morin.

In yet another study, the individual flavonoids baicalin and baicalein markedly increased ciclosporin levels in rats, whereas the root of baical skullcap, which contains these flavonoids, decreased the AUC of ciclosporin by up to 82%. In rats, ciclosporin halved the AUC of baicalin in blood, and increased its levels in bile by about 60%.

Mechanism

Flavonoids might affect ciclosporin levels by their effects on P-glycoprotein or the cytochrome P450 isoenzyme CYP3A4. In animal studies both increased and decreased levels have been seen.

Importance and management

Evidence for an interaction between flavonoids and ciclosporin is largely limited to experimental data. In the one clinical study, high-dose quercetin modestly increased ciclosporin levels. The interaction is not sufficiently severe to suggest that concurrent use should be avoided; however, it may make ciclosporin levels less stable as the quercetin content of different herbs and preparations is likely to vary. Concurrent use may therefore be undesirable. If concurrent use of ciclosporin and a quercetin-containing product is undertaken it should be monitored well.

In animal studies, both increases and decreases in ciclosporin levels have been seen with individual flavonoids. Until more is known, it may be prudent to be cautious with any flavonoid supplement and ciclosporin, especially those containing high doses. Although the reduced nephrotoxicity is interesting, this has to be viewed in the context of possible adverse pharmacokinetic interactions.

Flavonoids + Digoxin

The interaction between flavonoids and digoxin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in pigs, three animals were given digoxin 20 micrograms/ kg with quercetin 50 mg/kg and three animals were given digoxin alone. Unexpectedly, two of the pigs receiving the combination died suddenly within 30 minutes. At 20 minutes, the serum digoxin levels of the animals receiving the combination were 2.6-fold higher than those in the animals given digoxin alone (6.73 nanograms/mL versus 2.54 nanograms/mL). In a further crossover study in 4 pigs, quercetin at a slightly lower dose of 40 mg/kg increased the maximum level of digoxin fivefold and the AUC 2.7-fold. The authors state that they specifically chose pigs for this study, as a preliminary study suggested that the pharmacokinetics of digoxin in pigs were similar to that in humans.

Mechanism

Quercetin is suspected to increase the oral absorption of digoxin by inhibiting intestinal P-glycoprotein. A study investigating the effects of kaempferol derivatives isolated from Zingiber zerumbet, a species related to ginger, found that some of these derivatives inhibited P-glycoprotein, with a potency similar to verapamil, a known clinically relevant P-glycoprotein inhibitor. Kaempferol may therefore also raise digoxin levels.

Importance and management

Although there is just one animal study of quercetin, its findings of markedly increased levels of digoxin and toxicity suggest that caution would be appropriate with supplements containing quercetin in patients taking digoxin until further data become available. Monitor for digoxin adverse effects, such as bradycardia, and consider measuring digoxin levels if this occurs.

Note that there is currently no evidence of any clinically important interactions between digoxin and food, even for foods known to be rich sources of quercetin such as onions (about 7 to 34mg/100g), which suggests that any interaction might require very high doses. The only possible evidence identified was one early pharmacokinetic paper, which reported a modest 43% increase in the peak level of digoxin after administration of acetyldigoxin with carob seed flour, which is also a rich source of quercetin (about 39mg/100g).3

Flavonoids + Enalapril

The interaction between flavonoids and enalapril is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In rats, oral kaempferol 2 mg/kg and 10 mg/kg given with enalapril increased the AUC of enalaprilat (the active metabolite of enalapril) by 60% and 109%, respectively, but only the effect with 10 mg/kg was statistically significant. Naringenin 2 mg/kg and 10 mg/kg caused only a minor 18 to 38% increase in AUC of enalaprilat, which was not statistically significant.

Mechanism

In vitro, both kaempferol and naringenin were shown to be potent esterase inhibitors. Esterases hydrolyse enalapril in the gut: esterase inhibition by these flavonoids may be expected to increase the stability of enalapril, increasing its absorption.

Importance and management

Evidence appears to be limited to this experimental study. The effect of kaempferol would not be expected to be clinically important because enalapril has a wide therapeutic range. Naringenin does not appear to interact. No dosage adjustments would therefore be expected to be needed if either of these flavonoids is given with enalapril.

Flavonoids + Etoposide

The interaction between flavonoids and etoposide is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In an in vitro study using rat gut sacs, pre-treatment with quercetin or a natural diet (assumed to contain flavonoids) for 30 minutes increased etoposide absorption when compared with a flavonoid-free diet. However, there was no difference in etoposide absorption when rats were pretreated for one week with a natural diet (assumed to contain flavonoids) compared with a flavonoid-free diet.

In another animal study, oral morin given 30 minutes before etoposide increased the AUC of oral etoposide by about 46% but had no effect on the AUC of intravenous etoposide.

Mechanism

It is suggested that flavonoids might inhibit P-glycoprotein or the cytochrome P450 isoenzyme CYP3A4 in the gut, and thereby increase the absorption of etoposide, which is a substrate of CYP3A4 and/or P-glycoprotein.

Importance and management

A finding of a 50% increase in the AUC of etoposide might be clinically relevant in humans. However, these are animal data, and therefore some caution is required in extrapolating their findings. Also, the data suggest that the effect of continued use over one week might have little effect. Further study is needed before any specific recommendations can be made.

Flavonoids + Fexofenadine

Naringin and hesperidin may slightly reduce fexofenadine bioavailibility.

Clinical evidence

In a crossover study in 12 healthy subjects, fexofenadine 120 mg was given with either 300 mL of grapefruit juice, an aqueous solution of naringin at roughly the same concentration found in the juice (1 210 micromol), or water. The AUC of fexofenadine with grapefruit juice and naringin solution was reduced by 45% and 25%, respectively, when compared with water.

In another study in 12 healthy subjects, fexofenadine was given with grapefruit juice, or water, at the same time, or 2 hours before, an aqueous suspension of the particulate fraction of grapefruit juice. The particulate fraction (i.e. the solid matter after centrifugation of the juice) is known to be rich in furanocoumarins, which are clinical inhibitors of intestinal CYP3A4, but relatively low in naringin (34 micromol). The AUC of fexofenadine was reduced by 43% by grapefruit juice, but was not affected by the particulate fraction (when compared with water).

Experimental evidence

An in vitro study found that the flavonoids in grapefruit (naringin) and orange (hesperidin) were potent inhibitors of intestinal OATP transport.

Mechanism

The authors suggested that naringin directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability, and that inactivation of enteric CYP3A4 was probably not involved.

Importance and management

The small 25% reduction in AUC of fexofenadine with a high concentration of naringin is unlikely to be clinically important. No interaction would therefore be expected with naringin supplements. However, note that grapefruit juice and other fruit juices might cause clinically relevant reductions in fexofenadine levels in some individuals. See the table Summary of established drug interactions of grapefruit juice. Therefore an interaction with other extracts from these juices cannot be ruled out.

Flavonoids + Food; Milk

The addition of milk to tea did not alter the absorption of quercetin or kaempferol, or catechins, see Tea + Food.

Flavonoids + Herbal medicines

No interactions found. Flavonoids are a very large family of polyphenolic compounds synthesised by plants that are common and widely distributed.

Flavonoids + Irinotecan or Topotecan

Limited evidence suggests that high doses of chrysin are unlikely to cause an adverse interaction with irinotecan and possibly topotecan.

Clinical evidence

In a pilot study in patients with colorectal cancer receiving intravenous irinotecan 350mg/m every 3 weeks, chrysin 250 mg twice daily for one week before, and one week after, irinotecan appeared to be associated with a low incidence of irinotecan-induced diarrhoea. There was no difference in the pharmacokinetics of irinotecan and its metabolites when compared with historical data for irinotecan. Survival data did not differ from historical data suggesting that chrysin did not reduce the efficacy of irinotecan.However, note that this study was small and did not include a control group: therefore its findings require confirmation in a larger randomised study.

Experimental evidence

In vitro, chrysin has been found to be a potent inhibitor of the human transporter protein, BCRP. However, in a study in rats and mice, oral chrysin did not alter the pharmacokinetics of the BCRP substrate, topotecan. It was suggested that this may have been due to differences in rat and mouse BCRP compared with human BCRP.

Mechanism

The flavonoid chrysin possibly acts as an inducer of the metabolism of irinotecan by glucuronidases. It may also be an inhibitor of human BCRP.

Importance and management

The available data suggest that high doses of chrysin are unlikely to cause an adverse interaction if given with irinotecan, and might possibly be beneficial, but more study is needed to establish this. It is too early to say whether chrysin might affect topotecan pharmacokinetics, but the study does highlight a problem with extrapolating animal data to humans when studying this potential interaction.

Flavonoids + Paclitaxel

The interaction between morin, naringin or quercetin and paclitaxel is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

(a) Morin

The pharmacokinetics of paclitaxel were determined in rats after oral or intravenous administration of paclitaxel with or without morin (3.3 and 10 mg/kg). Compared with paclitaxel alone, morin, given 30 minutes before oral paclitaxel, increased the maximum levels and AUC of paclitaxel by 70 to 90% and 30 to 70%, respectively, without any change in the time to reach maximum levels, or elimination half-life. In contrast, the pharmacokinetics of intravenous paclitaxel (3.3mg/kg) were not altered significantly by morin.

(b) Naringin

A study to investigate the effects of oral naringin on the pharmacokinetics of intravenous paclitaxel in rats found that oral naringin (3.3 and 10mg/kg), when given to rats 30 minutes before intravenous administration of paclitaxel (3mg/kg), produced a significantly higher AUC for paclitaxel (about 41% and 49% for naringin doses of 3.3 and 10 mg/kg, respectively). Clearance was also delayed (29% and 33% decrease, respectively) when compared with the controls. In a similar study using oral paclitaxel, oral naringin increased the AUC of paclitaxel by up to threefold, and increased the elimination half-life. The oral bioavailability of paclitaxel increased from 2.2% up to 6.8%.

(c) Quercetin

In an animal study using oral paclitaxel, oral quercetin increased the AUC of paclitaxel by up to 3.3-fold, and increased the elimination half-life. The oral bioavailability of paclitaxel increased from 2% up to 6.6%.”

Mechanism

Paclitaxel is a substrate of P-glycoprotein and the hepatic cytochrome P450 subfamily CYP3A and isoenzyme CYP2C8. The flavonoids might inhibit the metabolism of paclitaxel by CYP3A and the transport of paclitaxel via intestinal P-glycoprotein, thereby increasing the AUC of paclitaxel. Note that there is evidence that quercetin does not inhibit CYP2C8, because it did not alter the metabolism of rosiglitazone, below, a specific substrate for CYP2C8.

Importance and management

The finding of increased oral absorption of paclitaxel with morin, naringin and quercetin is of little clinical relevance because paclitaxel is not used orally (it is poorly absorbed, even in the presence of the flavonoids).

Morin had no effect on the pharmacokinetics of intravenous paclitaxel, but the 50% increase in the AUC of intravenous paclitaxel caused by naringin would be clinically relevant in humans. However, these are animal data, and therefore some caution is required in extrapolating their findings. Further study is needed before any specific recommendations can be made.

Flavonoids + Quinine or Quinidine

The interaction between flavonoids and quinine or quinidine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In rats, naringin 25mg/kg daily for 7 days increased the oral bioavailability of a single 25-mg/kg oral dose of quinine from 17% to 42%, but did not affect the pharmacokinetics of intravenous quinine. In an in vitro study, quercetin and naringenin were modest inhibitors of quinine metabolism.

In another in vitro study, quercetin was an inhibitor of quinidine metabolism, with kaempferol and naringenin also having an effect,and, in rats, quinidine approximately halved the AUC of baicalin in blood, and increased its levels in bile by 47%.

Mechanism

Flavonoids are predicted to interact with quinine and quinidine via effects on cytochrome P450 isoenzymes or P-glycoprotein.

Importance and management

On the basis of animal and in vitro data, it is possible that high doses of quercetin, kaempferol and naringenin or naringin might increase quinine or quinidine levels, but any interaction is not firmly established. Furthermore, the rise in the quinine levels was modest, and unlikely to be clinically relevant if a similar effect were shown in practice. Note that grapefruit juice (a rich source of flavonoids), does not have a clinically relevant effect on the pharmacokinetics of quinine or quinidine. The clinical relevance of the effects of quinidine on biacalin disposition is unclear.

Flavonoids + Rosiglitazone

Quercetin does not appear to affect the pharmacokinetics of rosiglitazone.

Clinical evidence

In a crossover study in 10 healthy subjects, quercetin 500 mg daily for 3 weeks had no effect on the pharmacokinetics of a single 4-mg dose of rosiglitazone, or its principal metabolite N-desmethylrosi-glitazone.

Experimental evidence

No relevant data found.

Mechanism

Rosiglitazone is a specific substrate for the cytochrome P450 isoenzyme CYP2C8, and it therefore appears that multiple-dose quercetin has no clinically relevant effect on this isoenzyme.The rationale that it might was because, in vitro, quercetin inhibits the CYP2C8-mediated metabolism of a number of substrates including paclitaxel. However, in the case of paclitaxel (and possibly the other substrates), P-glycoprotein inhibition and CYP3A4 might also be important.

Importance and management

Although evidence appears to be limited to this one study, it is supported by in vitro data that suggest the absence of an interaction. No clinically important pharmacokinetic interaction would be expected with long-term use of quercetin supplements in patients taking rosiglitazone, and therefore no dosage adjustments would be expected to be needed.

Flavonoids + Saquinavir

Quercetin does not appear to affect the pharmacokinetics of saquinavir.

Clinical evidence

In a study in 10 healthy subjects, the pharmacokinetics of saquinavir 1.2 g three times daily (Fortovase; soft capsules) were not affected by the concurrent use of quercetin 500 mg three times daily for 8 days. Concurrent use of both products was well tolerated.

Experimental evidence

No relevant data found.

Mechanism

Based on other data for quercetin, it was suggested that this flavonoid might increase saquinavir levels by inhibiting P-glycoprotein, or by effects on the cytochrome P450 isoenzyme CYP3A4.

Importance and management

Although the study appears to be the only published data, the absence of an interaction is fairly well established. Quercetin is unlikely to have a detrimental (or beneficial) pharmacokmetic effect when used with saquinavir, and therefore no dosage adjustments would be expected to be necessary on concurrent use.

Flavonoids + Statins

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

Clinical evidence

No interactions found.

Experimental evidence

In rats, oral kaempferol and naringenin, given with lovastatin.

markedly increased the AUC of lovastatin acid. Increases were 2.7-fold and 3.5-fold with kaempferol 2mg/kg and 10 mg/kg, respectively, and 2.6-fold and 3.9-fold with naringenin 2mg/kg and 10 mg/kg, respectively. Other in vitro studies have shown that naringenin inhibits simvastatin metabolism.

Mechanism

Kaempferol and naringenin may be esterase inhibitors. In addition, naringenin may inhibit the cytochrome P450 isoenzyme CYP3A4, the main route of metabolism of simvastatin and lovastatin. Esterases hydrolyse lovastatin in the gut to lovastatin acid which is poorly absorbed: esterase inhibition by these flavonoids may be expected to increase the stability of lovastatin, increasing its absorption. Subsequent metabolism then leads to greater levels of lovastatin acid than would have occurred in the absence of the flavonoids.

Importance and management

There appears to be no clinical evidence to support these experimental findings of an interaction between kaempferol or naringenin and simvastatin or lovastatin. However, the marked increase in lovastatin levels that occurred with these flavonoids in the animal study, and the known important interaction of grapefruit juice (which is a rich source of flavonoids) with lovastatin and simvastatin (leading to rhabdomyolysis and myopathy), suggest that kaempferol and naringenin supplements should generally be avoided in patients taking these statins. This advice should be extended to citrus bioflavonoid supplements.

Flavonoids + Tamoxifen

The interaction between flavonoids and tamoxifen is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

(a) Antagonistic effects

Various flavonoids have been investigated in vitro for their ability to reduce the proliferation of cancer cells, and in vivo some studies have shown synergistic cytotoxicity with tamoxifen (e.g. with catechins).

In contrast, and of concern, it has been reported that tangeretin abolished the growth inhibitory effects of tamoxifen in mice, and shortened the survival time of tamoxifen-treated tumour-bearing mice compared with those receiving tamoxifen alone. This finding was not explained by changes in tamoxifen pharmacokinetics, see below.

(b) Pharmacokinetics

In a study, mice receiving tangeretin and tamoxifen had higher tamoxifen levels than those receiving tamoxifen alone. In addition, tangeretin did not alter the ratio between tamoxifen and its W-desmethyl metabolite.

In a study in rats, oral quercetin modestly increased the AUC of oral tamoxifen given concurrently. The effect was not dose dependent; there was a 35% increase with quercetin 2.5mg/kg, a 60% increase with quercetin 7.5 mg/kg and a smaller 20% increase with quercetin 15 mg/kg. There was also a minor 8 to 29% increase in the AUC of the active 4-hydroxytamoxifen metabolite. When compared with intravenous tamoxifen, quercetin 7.5 mg/kg increased the absolute oral bioavailability of tamoxifen by 60% (from 15% to 24%).

Mechanism

These findings suggest that quercetin inhibits both drug transporter proteins and possibly the cytochrome P450 isoenzyme CYP3A4, which decreases the first-pass metabolism of tamoxifen. The authors suggested that the antagonistic effect of tangeretin against tamoxifen was because tangeretin is an inhibitor of natural killer cell activity.

Importance and management

There do not appear to be any clinical data investigating the possible interactions between tamoxifen and flavonoids, and extrapolating the available animal findings to the clinical situation is difficult. Nevertheless, some caution is required if patients taking tamoxifen also take products containing tangeretin, because the effect of tamoxifen was abolished in one study, despite an increase in its levels. Studies are clearly needed that assess both efficacy and pharmacokmetic effects of the concurrent use of tangeretin and tamoxifen. The authors of the study with tangeretin suggested that the level of tangeretin used (human equivalent of about 280 mg daily) could not be obtained by eating citrus fruits or drinking juices. However, they advise caution with the use of products containing large amounts of citrus peel oil, and dietary supplements containing large amounts of citrus bioflavonoids as these could provide sufficient amounts of tangeretin to interact. Given the severity of the possible outcome, until more is known this seems prudent.