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Flavonoid-statin interactions causing myopathy and the possible significance of
OATP transport, CYP450 metabolism and mevalonate synthesis
Joshua Zechner1, Susan M. Britza1, Rachael Farrington1, Roger W. Byard1,2, and Ian F. Musgrave1
1. Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia
2. Forensic Science SA, Adelaide, SA, 5000, Australia
Corresponding Author:
Mr Joshua Zechner,
Faculty of Medical Science
Level 3 Medical School South Building,
The University of Adelaide, Frome Road,
Adelaide 5005, Australia
Email: joshua.zechner@adelalaide.edu.au
Word count: 4281
Abstract: 213
Figure count: 5
Table count: 1
Abstract:
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic
cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse
events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity
although it is theorised that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug
interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to
herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high
dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy.
This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion
transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase
which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose
flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA
reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed
throughout.
Keywords:
CYP450; OATP; Statins; Flavonoids; Myopathy; Herbal Supplements
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1. Introduction:
Hypercholesterolaemia is a condition characterised by high plasma levels of low-density lipoproteins (LDL) and low levels of
high-density lipoproteins. It is associated with a high risk of forming atherosclerotic plaques, thus resulting in potentially fatal
cardiovascular diseases[1]. The primary treatment for hypercholesteremia is statin therapy[2, 3]. Statins act by inhibiting the rate
limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase which causes reduced hepatic biosynthesis of
HMG-CoA into mevalonate, a crucial step in cholesterol synthesis[4]. By decreasing hepatic cholesterol LDL receptors are
induced through a feedback loop and therefore increased LDL uptake within the liver occurs[4, 5]. This results in reduced serum
levels of LDL, making statins an effective treatment for hypercholesterolaemia[6].
Cardiovascular diseases are estimated to cause 31% of deaths globally per year making them the leading cause of death according
to the World Health Organization[7]. To combat this, statin therapy has become the most commonly prescribed drugs in the
world. For example, in Australia statins are used by approximately 25% of the population aged 65-years or over, with atorvastatin,
rosuvastatin and simvastatin being the most prescribed[2, 8]. Patient mortality is estimated to be decreased by 31% and 40% for
stroke and myocardial infarction, respectively, by statin therapy[9, 10].
Statins are well tolerated but there are rare cases of statin-induced side effects such as myopathies which may progress to
potentially fatal rhabdomyolysis[11-15]. Myopathy is defined as muscular symptoms, such as pain and tenderness with elevation
of creatinine kinase plasma levels ≥10x the upper normal limit; rhabdomyolysis may be defined as muscular symptoms with renal
impairment and creatine kinase plasma levels ≥40x the upper normal limit[12, 15]. The incidence of statin-induced
rhabdomyolysis has been estimated to be approximately 0.40-1.10 in 10,000 person years[11-15]. Most statins have a comparable
potential for developing myopathy or rhabdomyolysis, however, cerivastatin which was removed from the market in 2001, has
been associated with more cases of myotoxicities[12, 14, 16]. The risk for statin-induced myotoxicity is increased with higher
blood plasma concentrations[13, 17].
2. Flavonoids:
Flavonoids are a broad class of phytochemicals containing many subclasses such as flavones, flavonols, isoflavones, flavanones,
chalcones and flavan-3-ols (Figure 1)[18]. These are abundant in nature, commonly occurring in plant material which includes
fruits, vegetables, and complementary medicines (Table 1)[18].
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Figure 1: Core flavonoid structure and 10 structures of different flavonoids. Adapted from Panche et al[18], Fan et al[19]
and Cione et al[20].
Within Australia it is estimated that 47.8%, 9.5% and 7.5% of people will use either vitamin/mineral supplements, western or
Chinese herbals or flower essences respectively, which are likely to contain flavonoids, this data could be considered to be
broadly representative of the western experience[21, 22]. The geriatric population seems to be the most vulnerable to flavonoid-
statin interactions. Not only are they the primary age group receiving statin therapy, but they are also more likely to be using
complementary medicines with approximately 25% reporting having used some form of complementary medicine in 2017[21,
23].
The average dietary daily intake of total flavonoids in Australia has been estimated to be 626 ± 579mg a day[24]. Dietary
flavonoids could modulate the pharmacokinetics of statins as reviewed by Peluso et al[25] but there has been few investigations
concerning the potential effects of co-administering high dose herbal supplements with statins, which can contain up to ≥1000mg
of flavonoids[26, 27].
Plasma concentrations achieved when taking high dose flavonoids are poorly understood even though high dose supplements are
readily available by over-the-counter sales. The studies that do exist do not investigate long term usage and co-administration with
other drugs.
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Table 1: List of flavonoids, their subclass, and some examples of flavonoid-containing plant sources
Flavonoid
Subclass
Plant
References
Apigenin
Flavone
Celery and garlic
Hollman and Arts[28].
Miean and Mohamed[29].
Biochanin A
Isoflavone
Red clover (Trifolium
pratense) and chickpeas
Křížová et al[30].
Gao et al[31].
Epigallocatechin Gallate
Flavan-3-ol
Green tea (Camellia sinensis)
and cocoa
Cione et al[20].
Genistein
Isoflavone
Soybean and chickpeas
Spagnuolo et al[32].
Hesperitin
Flavanone
Grapefruit, orange, lemon, and
bergamot
Gattuso et al[33].
Kaempferol
Flavonol
Spinach, cabbage, and
cauliflower
Sultana and Anwar[34].
Licochalcone A
Chalcone
Chinese liquorice (Glycyrrhiza
inflata)
Fan et al[19].
Luteolin
Flavone
Broccoli and bird’s eye chilli
Miean and Mohamed[29].
Naringenin
Flavanone
Grapefruit, orange, lemon, and
bergamot
Alam et al[35].
Gattuso et al[33].
Quercetin
Flavonol
Peas, onion, and apple
Sultana and Anwar[34].
Hollman and Arts[28].
3. Pharmacokinetic interactions:
3.1 CYP450 interactions
The statins simvastatin, lovastatin and atorvastatin are likely to be subject to drug-drug or herb-drug interactions involving
cytochrome 3A4 (CYP3A4) modulation[36, 37]. CYP3A4 inhibitors are known to raise the plasma concentrations of simvastatin
and atorvastatin[36, 37]. By reducing the metabolism of statins, CYP3A4 inhibitors increase statin systemic exposure and
therefore increase the chance for statin-induced myopathy[36-40]. This idea has been largely accepted by clinicians and
researchers though there are inconsistencies in the data. A large cohort study found a relative risk of 2.17 for hospitalisation due to
statin-induced rhabdomyolysis when concomitantly prescribed the potent CYP3A4 inhibiting antibiotics clarithromycin and
erythromycin compared to the non-inhibitor antibiotic azithromycin[38]. It should be noted that clarithromycin also exhibits
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strong inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) however the primary statin taken in this study was
atorvastatin, so the primary interaction was attributed to CYP3A4 inhibition[38, 41].
In contrast, a large retrospective study concluded that there was no significant difference for developing statin-induced myopathy
in the presence of a CYP3A4 inhibitor compared to statin therapy alone, this was regardless of the statin being a CYP3A4
substrate or not[42]. The primary concomitant drug taken in this cohort was diltiazem, a moderate CYP3A4 inhibitor that has
negligible effects on OATP1B1[42, 43]. Rowan et al[42] may have observed no significant differences between statin co-
administration and statin monotherapy as diltiazem might be too weak of a CYP3A4 inhibitor to cause significant adverse
reactions with statins or because statins are more likely to interact with inhibitors that target both CYP3A4 and transporters[42,
43]. For example, the in-vitro IC50 for CYP3A4 by diltiazem is reported to be between 110-127µM while the in-vitro IC50 for
CYP3A4 by clarithromycin IC50 is reported to be 56±5µM[44, 45]. This would need to be confirmed through further research.
Neither study investigated the concomitant use of herbal compounds[41, 42].
Many flavonoids have inhibited CYP3A4 in-vitro at comparable concentrations to clarithromycin. Naringenin was shown to
inhibit CYP450 metabolism of simvastatin with a Ki=25.48±10.10µM[46]. Biochanin A and genistein non-competitively inhibited
CYP3A4 with an IC50=65.11±3.97 and ~24.4µM respectively[47, 48]. Quercetin non-competitively inhibits CYP3A4 with an
IC50=5.5±0.7µM, making it one of the most potent inhibitors among the other flavonoids[49]. Epigallocatechin gallate (EGCG)
non-competitively inhibited CYP3A4 and CYP2C9 with IC50=23.7±1.54µM and 39.1±22.46µM, this would suggest that EGCG
would be likely to interact with fluvastatin, rosuvastatin, pravastatin and pitavastatin[50].
There are a limited number of studies investigating the co-administration of high dose flavonoids with statins in humans. A study
in rats receiving intravenous EGCG at 5mg/kg found that the area under the curve (AUC) of simvastatin and its metabolite
simvastatin acid were raised by 2.2 and 1.4-fold respectively[48]. This was likely due to EGCG inhibiting both CYP3A4
metabolism and OATP-uptake[48]. Similarly, 16 male humans co-administered 500mg of quercetin and pravastatin for 14 days,
had an increase in AUC of 1.24-fold compared to pravastatin alone[51]. The authors of this study did not investigate the
significance of CYP3A4, but it seems likely that OATP1B1 or CYP2C9 inhibition are the primary factors leading to increased
pravastatin serum levels as it is not susceptible to CYP3A4 interactions[37, 51].
3.2 OATP interactions
While the inhibition of CYP450 metabolism of statins has historically been the primary focus when investigating statin-induced
myopathy in more recent years inhibition of OATP uptake has been identified as an important risk factor. The significance of
inhibited OATP1B1 function in statin-induced myopathy has been highlighted in large genome studies. Those with the rs4149056
single nucleotide polymorphism within the SLCO1B1 gene that encodes OATP1B1 have reduced OATP1B1 statin uptake and
therefore reduced hepatic clearance of statins, with simvastatin being the most affected [17, 52]. Those taking 40mg of simvastatin
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every day who were homozygous for this polymorphism had an odds ratio of 4.5 (CI 2.6-7.7) for developing myopathy, compared
to those without[17]. The review by Niemi[52] summarises that those homozygous with this polymorphism had an AUC increase
after a single dose of simvastatin, pitavastatin, atorvastatin, pravastatin or rosuvastatin by 2.21-fold, 1.62-1.91 – fold, 1.44-fold,
0.57-1.30 – fold, 0.62-1.17 – fold respectively[52]. There was no significant effect by fluvastatin[52].
Much like the genomic studies, large cohort studies have identified the dangers of concomitant use of OATP1B1 inhibitors with
statins. For example, Gemfibrozil is an OATP1B1 inhibitor that has minimal effects on CYP3A4 and a potent inhibitory effect on
CYP2C9[53, 54]. It was found that those taking gemfibrozil with a statin had a calculated incidence rate ratio of 11.93 (CI 3.96-
35.93) for being hospitalised due to rhabdomyolysis compared to those taking a statin alone[55]. These results were similar to
those of Graham et al previously[13].
Recently a study investigating the effects of 99 flavonoids on OATP1B1 uptake of statins found that 8 flavonoids significantly
inhibited the uptake of fluvastatin[19]. The three most potent inhibitors were licochalcone A (IC50 = 7.96 μM), luteolin
(IC50 = 22.03 μM) and biochanin A (IC50 = 22.28 μM)[19]. Wang et al[56] found the most potent inhibitors of OATP1B1-
mediated uptake of [3H]dehydroepiandrosterone sulphate, to be biochanin A, genistein and EGCG with IC50=11.3±3.22µM,
14.9±3.76µM and 14.1±1.44 µM respectively. They also found the mechanism to be non-competitive inhibition[56]. Mandery et
al[57] found the flavonoids quercetin, kaempferol and apigenin exhibited competitive inhibition of OATP1B1. The Ki values for
quercetin, kaempferol and apigenin for the OATP1B1-mediated uptake of bromosulfophthalein were 8.8±0.8µM, 32.4±2.2µM and
53.4±2.1µM, respectively[57]. The authors[57] repeated these tests on the uptake of atorvastatin and interestingly found that the
Ki for apigenin had become 0.6±0.2µM while quercetin and kaempferol had remained relatively unchanged[57]. They suggest that
apigenin may form different inhibitor-receptor complexes dependent on the substrates. Further studies should be done to
investigate if flavonoids have differing inhibitory affinities with different statins.
It is difficult to say what flavonoids pose a greater risk for developing statin-induced myopathy until further studies are conducted
investigating flavonoid interactions for all statins. Though the pleiotropic inhibitory effects of flavonoids would put them at risk of
interacting with a range of statins.
4. Statin pharmacokinetics and drug interactions:
Plasma concentrations of statins are a result of the balance between cellular uptake and metabolic breakdown. Most statins rely on
OATP uptake, for cellular uptake and are metabolised by CYP450 in the liver[58, 59]. Simvastatin, lovastatin, and atorvastatin are
CYP3A4 substrates, while fluvastatin, rosuvastatin, pravastatin and pitavastatin are CYP2C9 substrates[37, 40, 59, 60].
Hydrophilic statins such as rosuvastatin and pravastatin are primarily dependent on OATP1B1 for entry into cells while lipophilic
statins can permeate through cell walls, though OATP1B1 still plays a role[58, 60].
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Genetic polymorphisms with reduced CYP450 metabolism or OATP1B1 uptake, or concomitant use of drugs that inhibit these
processes can result in increased plasma statin concentrations and myopathy[13, 17, 36, 37, 39, 40]. For example, the fibrate,
gemfibrozil and the macrolide antibiotic, clarithromycin (OATP inhibitor and combined OATP and CYP450 inhibitor,
respectively) induced rhabdomyolysis when co-administered with statins[13, 38, 55].
5. Mechanisms of myotoxicity:
Currently no mechanism for statin-induced myopathy has been established though there are many hypotheses. Two of the leading
hypothesised mechanisms include dysfunctional mitochondria or decreased prenylation due to the inhibition of the HMG-CoA
pathway[60-62].
Evidence for the dysfunctional mitochondrial theory is linked to decreased coenzyme Q10 (CoQ10) levels which disrupt
mitochondria within skeletal muscle, releasing free radicals and thus resulting in myotoxicity (Figure 3)[61]. CoQ10 is a
downstream product of the HMG-CoA pathway which plays an important role in electron transport within the mitochondrial
respiratory chain[61]. It has been noted that there is a decrease in CoQ10 in serum levels of patients with muscle diseases[63].
Some studies as reviewed by Deichmann, Lavie and Andrews[61] have reported that statin users have had decreased CoQ10
serum levels and have suggested that this is a potential mechanism for statin-induced myotoxicity others have not found a link
between statin induced falls in CoQ10 serum levels and mitochondrial dysfunction. Many small-scale studies supplementing
CoQ10 within those suffering from statin-induced myotoxicity produced inconsistent results and therefore it has been accepted
that there is currently insufficient data to state whether CoQ10 is an underlying mechanism to statin-induced myopathy[61, 62].
Figure 2: Decreased CoQ10 disrupting mitochondria in skeletal muscle cell, hypothetically causing myotoxicity[61]
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The hypothesis for statin inhibition of protein prenylation as a cause of myotoxicity is associated with decreased levels of
Geranylgeranyl pyrophosphate (GGPP). GGPP is a downstream product in the HMG-CoA pathway and plays a role in prenylation
of proteins which are vital for cell function[64]. In-vitro studies have found that statin use will inhibit GGPP activity and therefore
disrupt GTPases such as RhoA and Rab which require prenylation for cell membrane anchorage (Figure 3)[65, 66]. RhoA plays a
role in the cytoskeleton of myocytes by allowing actin to form stress fibres, while Rab is important in regulating vesicle transport
within the cytoplasm, both vital roles for cell survival (Figure 5)[66-68]. Sakamoto[66] and colleagues identified that fluvastatin
and pravastatin-inhibition of Rab lead to morphological changes of myocyte organelles including mitochondria thus ultimately
causing cell death, moreover, these morphological changes were attenuated in the presence of GGPP. Itagaki et al[65] found that
simvastatin and fluvastatin, but not pravastatin, induced skeletal muscle apoptosis in rats by caspase-3 activation. The authors
observed that RhoA had been displaced from the cell membrane into the cytosol and theorize that this may be an underlying
mechanism for the observed statin-induced myotoxicity as both apoptosis and RhoA displacement were attenuated in the presence
of GGPP[65].
Figure 3: Decreased GGPP resulting in decreased Rab and RhoA prenylation hypothetically resulting in decreased vesicle
membrane anchorage or actin stress fibre formation and cytoskeleton organisation respectively which both ultimately lead
to myotoxicity[65-67].
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6. Pharmacodynamic interactions:
Flavonoids have been studied as potential HMG-CoA reductase inhibitors with the expected outcome that they may have less
adverse reactions than statins while effectively treating hypercholesteremia[69]. It is proposed, however, that the inhibition of the
HMG-CoA pathway may lead to myotoxic events which is why careful attention should be paid to high dose flavonoid intake and
muscle toxicities in animal and human trials. Currently there are some studies trying to elucidate the relationship of flavonoids
with HMG-CoA through molecular docking in-silico[70-72].
The flavonoids quercetin, EGCG and biochanin A inhibit HMG-CoA reductase directly or indirectly[70, 71, 73]. EGCG potently
binds to HMG-CoA reductase in liver microsomes with a Kd of 77.0 ± 12.0 nM through an allosteric site on HMG-CoA
reductase[71]. When EGCG is co-administered with pravastatin, a synergistic interaction achieves greater inhibition than
monotherapy with either compound[71]. Quercetin was found to inhibit HMG-CoA reductase by binding directly to the substrate
binding site with a more moderate binding affinity (Kd=38.8±13.2µM) in cultures of the human liver cancer cell line known as
HepG2 cells[70]. Whereas biochanin A indirectly inhibits HMG-CoA reductase activity by decreasing levels of mRNA for HMG-
CoA reductase and sterol regulatory element-binding protein 2, an important stimulus for HMG-CoA reductase activity[73].
Conjugate forms of the flavonoids naringenin and hesperetin contain HMG-CoA like moieties and modelling suggests are capable
of directly binding to the substrate site of HMG-CoA reductase resulting in inhibition, though their efficacy compared to statins is
yet to be determined experimentally[72].
Hypothetically if the inhibition of mevalonate synthesis is a risk factor for developing myopathy, high doses of flavonoids may be
contraindicated with statin therapy. Further studies are needed to evaluate combined therapy of flavonoids and statins, measuring
HMG-CoA reductase activity and testing whether these findings are constrained to in-vitro or in-silico settings.
7. Statin adverse events and phytochemical interactions:
Complementary medicines have been scrutinised less closely than conventional medicines for adverse reactions. The Australian
population has a high level of use of complementary medicines with the local industry estimated to be worth billions of dollars[21,
74]. Herbal medicines are one of the many forms of complementary medicines with 9.5% of Australians reporting use of herbal
products over a 12-month period[21]. Certain foods and herbal supplements have been shown to have severe adverse effects when
taken concomitantly with drugs, with the classic example being grapefruit juice[75]. It is known that consuming grapefruit with
either simvastatin, lovastatin or atorvastatin can raise statin serum levels, increasing the risk for statin-induced myopathies[75].
Citrus fruit juices such as grapefruit and lemon juice inhibit CYP3A4, and more recently has been shown to inhibit OATP1B1[57,
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75, 76]. While grapefruit juice inhibition of CYP3A4 is due to furanocoumarins37, inhibition of CYP3A4 by other citrus fruit
juices and OATP1B1 by fruit juices generally has been attributed to a class of phytochemicals known as flavonoids[57, 76].
There are approximately 5000 known flavonoids that are found in foods and herbal supplements[77]. Flavonoids have been
investigated for potential therapeutic properties for a range of medical conditions and events such as cancer, menopause, and
cardiovascular disease[78, 79]. However, these herbal supplements need to be approached with caution as very little is known
about their pharmacological impact and how flavonoids may interact with medications at high dosages.
In terms of statins In-vitro studies have demonstrated that some flavonoids can inhibit both CYP450 and OATP1B1 (Figure 4)
which may have implications for statin pharmacokinetics, possibly leading to adverse events when concomitantly used with
statins at large doses[47, 56, 57, 80-82]. In vitro studies suggesting interactions are reinforced by animal and human trials that
have reported increased statin blood concentrations in those taking flavonoids[46, 48, 51, 57, 75].
Figure 4: Flavonoids inhibit hepatic OATP1B1 uptake and CYP450 metabolism of statins raising statin blood
concentration levels and potentially leading to muscle toxicity
Additionally, flavonoids can inhibit HMG-CoA reductase to varying degrees which is a proposed pathway in the development of
statin-induced myopathy, as described in the previous section, suggesting the potential for pharmacodynamic interactions (Figure
5)[70, 71, 73].
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Figure 5: Statins and flavonoids both inhibit HMG-CoA reductase inhibiting coenzyme Q10 and geranylgeranyl
pyrophosphate which may lead to muscle toxicity
Finally, it has also been reported that polypharmacy of flavonoids increases their bioavailability, thus increasing systemic
exposure[81, 83].
Flavonoid rich foods and statin interactions have been reviewed by Peluso et al[25] but currently there is a lack of data
surrounding concomitant use of statins with herbal supplements, specifically those with high doses of flavonoids that inhibit both
CYP3A4 and OATP1B1 and the potential resultant adverse events. This review will summarise what is currently known about
flavonoids potential to interact with statins through hepatic OATP1B1 and CYP450 modulation as well as through the inhibition
of cholesterol synthesis. P-glycoprotein may also play a role but will not be covered in this review[84, 85].
8. Plasma flavonoid concentrations achievable via supplements:
Although flavonoids can potentially affect both the pharmacodynamics and pharmacokinetics of statins, the question arises as to
whether oral consumption of supplements will achieve the required concentrations in the body to produce adverse effects. EGCG
and quercetin are common flavonoids used in supplements likely to be consumed by people on statins, possibly even combined,
and examining their plasma concentrations may give some insight into the potential risk of interactions.
In fasting subjects EGCG reached a peak blood plasma level of 7.4 ± 3.6 µM after consuming a single dose catechin mixture
containing 1,200 mg EGCG[86]. Fed subjects achieved a lower plasma concentration of 2 ± 1.7 µM with the same dose[86]. The
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high variability seen in this study is mirrored in another study following a large cohort taking either 0, 500mg or 1000mg of
quercetin as twice daily doses over 12-weeks saw large interindividual variation with peak blood plasma concentrations ranging
from 0-2.98 µM[87]. As the variations appeared to be idiosyncratic the authors speculated that differing transporter genotypes or
dietary intakes may play a role[87].
In terms of the potential inhibition of statin metabolism, peak EGCG concentrations in fasted subjects are 3 times lower than the
IC50 for CYP3A4, and peak fed concentrations around 10 times less, suggesting acute ingestion of even high levels of
supplements by themselves will not greatly alter statin concentrations[50, 86]. Chronic consumption of quercetin supplements
achieves plasma levels around the Ki for CYP3A4 (2.98 µM compared with Ki of 5.5 µM)[87, 88].
In contrast EGCG may produce plasma levels sufficient to inhibit OATP (7.4 µM vs IC50 of 14.1 µM) while quercetin was well
below the Ki for OATP1 (53.4 µM)[56, 86]. Nonetheless, administration of 500 mg quercetin once a day for 14 days with
pravastatin increased Cmax of pravastatin by 131%[51]. As many quercetin supplements are dosed at 500mg/day or greater
showing the potential for induction of adverse effects.
Furthermore, flavonoids are often given in combinations which may increase their impact of statin metabolism.
9. Herbal medicine composition and plasma flavonoid concentrations:
Herbal medicines are very complex as they may contain hundreds to thousands of compounds. It is often difficult to discern what
precise compounds are present and physiologically active due to collectively-labelled ingredients. For example, flavonoid
supplements may have their ingredients broadly listed as flavonoids or bioflavonoids, making it difficult for researchers to identify
potentially harmful ingredients.
To add further complexity, flavonoids occur with additional sugar moieties (this structural form is known as either a glucoside or
a glycoside) in plant material which have modified absorption within the intestine compared to their aglycone counter parts[89,
90]. An example of this was observed when human subjects consumed 300mg of a quercetin glucoside a naturally occurring
conjugate form of quercetin, quercetin-4’-O-β-D-glucoside[91]. This resulted in mean peak plasma quercetin levels of
9.72±1.38µM which is approximately three times higher than Jin et al[87] observed, as quercetin in its glucoside or glycoside
form appears to have favourable absorption in the intestinal membrane[87, 89-91].
Additionally, there is evidence that polypharmacy of flavonoids can increase flavonoid concentrations, further complicating
flavonoid-statin interactions. In-vitro it was observed that the amount of biochanin A present in the human colorectal
adenocarcinoma cell line, Caco-2 cells and HepG2 cells was increased by 1.51 and 3.06 times respectively in the presence of
quercetin and EGCG respectively, with significantly decreased conjugation in the caco-2 cells[81]. In-vivo it was found that
EGCG and quercetin promoted enterohepatic recycling of biochanin A, therefore increasing its systemic exposure[81]. The
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authors proposed that multiple mechanisms, including inhibition of conjugation, CYP450s and efflux transporters involved in the
metabolism and excretion of biochanin A were responsible[81]. This is of importance as these flavonoids commonly occur within
the diet and have been investigated for treating cardiovascular diseases, potentially increasing the risk of being combined with
statins[92-94].
The more realistic approach of combined oral administration of flavonoids that commonly occur together in the diet or in
supplements highlights that flavonoid blood plasma concentrations may reach higher than expected level due to pharmacokinetic
interactions amongst each other[81]. Further research investigating whether flavonoids with high inhibitor constants for pathways
not only important for statin pharmacokinetics, but also other flavonoid pharmacokinetics are needed to see if the polypharmacy
of flavonoids can result in flavonoid-flavonoid interactions thus potentiating statin-flavonoid interactions.
10. Discussion:
Statins are the primary treatment for hypercholesterolaemia and the cessation of therapy due to unexplained statin intolerance
could be life threatening[8-10]. There is a risk of flavonoids being co-administered with statins as not only are they abundant in
the diet, but high dose supplements are also available for several conditions including cardiovascular diseases[69, 78, 79]. Despite
little evidence for them acting therapeutically.
Older Australians appear to be the most vulnerable to flavonoid-statin interactions as they are likely to use both statins and
supplements (such as bioflavonoid antioxidants) which can contain concentrations of flavonoids capable of inhibiting the uptake
and metabolism of statins[8, 21]. There are many studies focusing on statin-drug reactions, but it is uncommon for them to include
herbal supplement usage[13, 38, 42, 55]. Supplement intake should certainly be recorded while on life-saving medications to
allow retrospective studies to investigate all possible causes for discontinuation.
Though limited in size, several human trials investigating statin-flavonoid use found increased statin serum levels with some
statins, potentially raising the risk for statin-induced myopathy[48, 51]. Furthermore, while flavonoids such as quercetin, luteolin,
EGCG and biochanin A have been studied there are many more flavonoids that have not been studied available for purchase at
higher dosages than the studied flavonoids that have produced statin interactions.
Raised statin plasma levels are likely due to flavonoids inhibiting CYP3A4, CYP2C9 and OATP1B1[19, 46-50, 56, 57]. Among
the flavonoids studied, the most potent inhibitor for OATP1B1 was licochalcone with an IC50 = 7.96μM. Licochalcone is not sold
as a pure supplement but is present in Chinese liquorice (Glycyrrhiza inflata) herbal supplements.
Quercetin was the most potent inhibitor of CYP3A4 with an IC50 of 5.5±0.7µM while EGCG also inhibited CYP2C9 with an IC50
of 39.1±22.46µM [19, 49, 50]. The IC50 concentration for quercetin on CYP3A4 can be achieved in plasma after oral ingestion of
300mg of quercetin-4’-O-β-D-glucoside[91]. As many quercetin containing supplements have between 250-800 mg of quercetin
15
per dose there is significant potential for CYP3A4 inhibition. There is a lack of data pertaining to whether the IC50 values of
licochalcone and EGCG can be achieved while taking high dose supplements. Furthermore, data on the effect of supplements
containing multiple flavonoids is not available even though synergistic interactions are possible.
These flavonoid IC50 values are comparable to that of the known OATP1B1 and CYP3A4 inhibitor clarithromycin and thus
suggest a high risk of clinically important interactions, especially in those whose genetic background puts them at risk. Further
investigations should evaluate a range of flavonoids with each statin to find high risk flavonoid-statin combinations.
Additionally, the inhibition of HMG-CoA reductase may lead to pharmacodynamic interactions between flavonoids and statins.
The downstream products of mevalonate, CoQ10 and GGPP have been theorized to play a role in statin-induced myopathy[61, 65,
66]. The flavonoids quercetin, EGCG and Biochanin A as well as conjugates of naringenin and hesperitin have all been shown to
either directly or indirectly inhibit HMG-CoA reductase[70-73]. EGCG seems to be of major concern as it has a high binding
affinity of Kd=77.0 ± 12.0nM and can act synergistically with pravastatin[71]. Hypothetically EGCG could inhibit CoQ10 and
GGPP which could imply that the EGCG is capable of myopathy itself or promoting statin-induced myopathies. This would need
to be investigated in myocyte cultures in the presence and absence of either CoQ10 or GGPP. Quercetin and the conjugates of
naringenin and hesperitin bind directly to the substrate binding site of HMG-CoA reductase which may competitively inhibit
statin binding, but this would require further testing to confirm[70, 72].
Some of the major difficulties researchers experience when exploring the safety of herbal supplements is unclear labelling of the
ingredients present in supplements as well as there being many different compounds present in these products. There are very few
regulations surrounding ingredients lists for herbal supplements of flavonoids allowing for collective-labels such as flavonoids
and bioflavonoids which makes it difficult to identify harmful flavonoids in these supplements. Flavonoids can occur in different
compositions such as aglycones, glucosides and glycosides which can have differing bioavailabilities as mentioned above[89-91].
There is also evidence that flavonoid-flavonoid interactions can occur such as those seen in the Moon and Morris’[81] study
showing that biochanin A in the presence of quercetin and EGCG produced higher plasma levels than biochanin alone.
In conclusion, herbal supplements should be scrutinised more closely when there is evidence of physiological activity but lack of
evidence for safety, especially when co-administered with conventional medicines. Flavonoid dietary intake may not be an issue
with statins. However, high dose supplements that greatly exceed the average dietary flavonoid intake are available and their
concomitant use with statins remains to be fully understood[30]. Furthermore, there is evidence that suggests clinically significant
interactions are possible.
Author contributions:
J. Z. prepared and wrote the first draft. S. M. B., R. F., R.W.B., and I. F. M. critically revised the draft. All authors approved the
final version.
16
Declaration of competing interest:
The authors declare that there are no conflicts of interest.
Acknowledgements:
Supported by the University of Adelaide Postgraduate Student Support (project ID: 15116917). J. Z. holds a University of
Adelaide PhD scholarship. The University of Adelaide did not direct the conduct or interpretation of this research.
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