Hypericum perforatum: Pharmacokinetic,Mechanism of Action, Tolerability, and ClinicalDrug–Drug Interactions
Emilio Russo,1,2* Francesca Scicchitano,1,2 Benjamin J. Whalley,3 Carmela Mazzitello,1,2Miriam Ciriaco,1,2 Stefania Esposito,1,2 Marinella Patanè,1,2 Roy Upton,4 Michela Pugliese,5Serafina Chimirri,1,2 Maria Mammì,1,2 Caterina Palleria1,2 and Giovambattista De Sarro1,21Science of Health Department, School of Medicine, University of Catanzaro, Catanzaro, Italy2Pharmacovigilance’s Center Region Calabria, University Hospital Mater Domini, Catanzaro, Italy3School of Chemistry, Food and Nutritional Sciences, and Pharmacy, The University of Reading, Whiteknights, Reading, BerkshireRG6 6AP, UK4American Herbal Pharmacopoeia, Scotts Valley, CA, USA5Department of Veterinary Science, University of Messina, Messina, Italy
A growing percentage of the population uses herbalproducts for preventative and therapeutic purposes.Several reasons for this wide usage have been proposedand include (i) the erroneous notion that, being ofnatural origin, herbals are safer than conventional med-icines; (ii) the philosophical belief that naturally deriveddrugs are more consistent with individual personalvalues; (iii) individuals’ desire for personal control overtheir health; and (iv) hard-to-treat conditions for whichconventional therapies are unavailable (Cheung et al.,2007; Cauffield, 2000). However, such lay beliefs beliethe evidence that herbal drugs cause significant sideeffects either individually or due to herb–drug interactions(Bent, 2008; De Smet, 2007; Ernst, 1998).Hypericum perforatum (HP), or St John’s wort, is a
plant whose extract, one of the best- characterised herbalmedicines, is widely sold in health food stores andpharmacies in Europe and the USA (annual US salesincreased from $20m in 1995 to $200m in 1997) for the
ondence to: Prof. Emilio Russo, Ph.D., Chair of Pharmacology,nt of Science of Health, School of Medicine, University of, Via T. Campanella, 115, 88100 Catanzaro, [email protected]
treatment of depression (Lecrubier et al., 2002; Kasperet al., 2006). Preclinical studies on the central nervoussystem activity of HP extracts suggest that it also displaysanxiolytic, sedative, nootropic, antischizophrenic, anti-convulsant, antidiabetic, and analgesic activities andthat it may be beneficial in the treatment of alcohol,nicotine, and caffeine addiction in experimental animals(Can et al., 2011; Can and Ozkay, 2012).
Recent clinical studies found HP extracts to beefficacious and well tolerated in the treatment of mildto moderate depressive episodes and for the short-termtreatment of symptoms in mild depressive disorders(Chen et al., 2011; Kasper et al., 2010). Moreover, HPextracts can be effective in the treatment of generalisedanxiety disorder, somatoform disorders, sleep disorders,obsessive–compulsive disorder, and seasonal affectivedisorder (Can et al., 2009).
Although >150 discrete ingredients that exhibit manyadditive, synergistic, and partly antagonistic effects havethus far been identified in this plant (Butterweck andSchmidt, 2007), HP’s most characteristic constituents arenaphthodianthrones (hypericin and pseudohypericin) andphloroglucinols (hyperforin and adhyperforin) (Butterweckand Schmidt, 2007; Nahrstedt and Butterweck, 1997),where hypericin is considered to be the most important
active ingredient although its concentration varies be-tween different parts of the plant (0.02–2.5%). However,hypericin has only been shown to have activity (e.g.monoamine oxidase inhibitor) in vitro and has failed toexert detectable effects in animal models. In Germany,HP has been approved by the Commission E since 1984for the treatment of anxiety, depression, and insomniaalthough interest in HP has primarily focused upon itsantidepressant effects. Additionally, numerous studieshave supported wound-healing effects (Negrash andPochinok, 1972; Rao et al., 1991; Šaljić, 1975), antimicro-bial properties (one of the oldest historical uses of HP,predominantly as St John’s wort oil) against a number ofbacterial and fungal strains (Saddiqe et al., 2010; Gaindand Ganjoo, 1959; Khosa and Bhatia, 1982; Shakirovaet al., 1970; Negrash and Pochinok, 1972; Brondz et al.,1982; Gibbons et al., 2002; Saroglou et al., 2007), andantiviral activity (Meruelo et al., 1988).Experimentally,HP extracts and one isolated constituent,
hyperforin, inhibit reuptake of several neurotransmitterssuch as serotonin, noradrenaline, dopamine, glutamate,and gamma-aminobutyric acid in vitro and in vivo(Capasso et al., 2003), many of which are involved in theregulation of mood, motivation, and reward. Subchronictreatment with an HP extract caused downregulation ofβ-adrenergic receptors (De Marchis et al., 2006), and theextract alters animal behaviour not only in several antide-pressant models (e.g. forced-swimming test), consistentwith the effects of conventional antidepressants (e.g.fluoxetine; De Marchis et al., 2006; Butterweck, 2003),but also in a chronic stress, mouse model (Crupi et al.,2011) and exerts anxiolytic and antipanic effects upon ratstested using the elevated T-maze, an animal model ofinnate (panic) and learned (generalised) anxiety (Beijaminiand Andreatini, 2003). However, extracts almost devoidof hyperforin have also demonstrated clinical efficacy(Schrader, 2000), suggesting that hyperforin is not solelyresponsible for the extract’s effects.Mild adverse effects attributed to HP have occasionally
been reported and include gastrointestinal complaints,tiredness, dizziness, and allergic and photosensitivityreactions (typically only at doses above 11.25mg of totalhypericin; Nahrstedt and Butterweck, 1997; Hendersonet al., 2002; Zhou and Lai, 2008).Furthermore and particularly given its nonprescrip-
tion nature, HP is often taken in combination with otherconventional medicines, creating the potential for herb–drug interactions (Hu et al., 2005; Izzo, 2012), theprevalence of which may be hard to quantify given thelay belief that ‘natural products are safe’ and so may leadto under-reporting of their use to clinicians. Commondrugs that interact with HP include anticoagulants, anti-convulsants, anti-HIV drugs, antidepressants, immuno-suppressant agents, antimicrobial drugs, hypoglycaemicdrugs, and oral contraceptives (Borrelli and Izzo, 2009;He et al., 2012) where their areas under the plasmaconcentration–time curve (AUC) and mean/peak bloodconcentrations are decreased (Borrelli and Izzo, 2009).However, from extant case reports, despite noted changesin the pharmacokinetic parameters of some of these drugs(e.g. digoxin and oral contraceptives), no changes topharmacodynamic effects have been found.Hypericum perforatum extracts are powerful activa-
tors of the enzyme CYP3A4 (Hemeryck and Belpaire,2002) and also increase the activity of the P-glycoprotein(P-gp), an adenosine triphosphate-dependent drug
transporter responsible for increased drug excretion(Hemeryck and Belpaire, 2002; Müller, 2003; Izzo, 2004).Most commercially available drugs are substrates forCYPs and/or P-gp, and some have low therapeutic indices,making interactions affecting available drug potentiallydangerous via either a loss of therapeutic effect or theinduction of toxicity.
In this review, we summarise HP’s known pharmacoki-netic and pharmacodynamic properties before criticallyconsidering its tolerability and the potential or knownHP–drug interactions.
PHARMACODYNAMICS ANDPHARMACOKINETICS OF HYPERICUMPERFORATUM
As previously stated, HP is most widely used for eitherthe treatment of depressive syndromes or antiviral/antiretroviral effects, although the literature reveals usesof this plant for other pharmacological and medicalpurposes (Table 1).
The pharmacokinetics of hyperforin, hypericin, andpseudohypericin, the components of HP extracts thatare presumed to be responsible for its pharmacologicaleffects, has been studied in detail in both animals andhumans (Butterweck, 2003; Caccia and Gobbi, 2009;Wurglics and Schubert-Zsilavecz, 2006). Despite struc-tural similarity (Fig. 1), hypericin, pseudohypericin,and hyperforin exhibit pharmacokinetic differences(Table 2). The pharmacokinetics of these componentswas studied in healthy volunteers after administrationof HP dry extract. After oral administration of singledoses (range = 300–1800mg ) of HP extract (0.3% ofhypericin), hypericin was detectable in the blood after1.3 h, and peak plasma concentrations were reachedafter ~4.6 h and steady-state levels by 4days (Brochmolleret al., 1997; Staffeldt et al., 1994; Upton, 1997). The plasmahalf-life of hypericin is reported to be ~25h (Nangia et al.,2000), the prolonged duration of which is due tohypericin’s affinity for albumin and lipoproteins (Bianchiet al., 1997). Although the bioavailability of hypericin is~14%, the therapeutic concentration of hypericin in brainremains unknown, and although it has been suggested thatbrain levels reach only 5% of plasma levels, hypericin’shalf-life in the brain may be weeks (Upton, 1997).
Pharmacokinetic studies have also been conductedusing a well-characterised pharmaceutical HP extract(LI 160; Lichtwer Pharma, Berlin, Germany) that con-tains 300-mg dry HP extract standardised to 0.24–0.32%hypericins (hypericin and pseudohypericin). Single oraldoses of 300, 900, and 1800mg were administered orallyto 12 healthy subjects, and peak plasma concentrationsof pseudohypericin of 2.7, 11.7, and 30.6 ng/ml, respec-tively, were found after 0.4–0.6 h (Staffeldt, 1994). Subse-quently, it was reported that after oral administration of300, 600, and 1200mg of two different ethanolic HPextracts (containing 5%and 0.5%hyperforin), hyperforinpeak plasma levels were reached after 2.8–3.6 h (Table 2).Here, hyperforin pharmacokinetics was linear fordoses up to 600mg whereas higher doses producedlower-than-expected plasma concentrations after linearextrapolation. In a study employing repeated doses,hyperforin accumulation was not be detected; steady-state plasma concentration after 900mg/day of extract
Table 1. Suggested pharmacological mechanisms of actions of Hypericum
Activity of Hypericum Mechanism of action Reference
Antidepressant Inhibition of monoamine oxidase (MAO) by hypericin Suzuki et al., 1984; Bladt and Wagner,1994; Bombardelli and Morazzoni, 1995;Chatterjee et al., 1998a, 1998b; Thiedeand Walper, 1994
Inhibition of MAO by the fraction of flavonoids in theextract of Hypericum (39%) structurally similar tothe MAO inhibitorsSuppression of the release of interleukin 6, asubstance related to depression as it modulates therelease of cortisolInhibition of reuptake of serotonin, norepinephrine,dopamine, and gamma-aminobutyric acid by hyperforinInhibition of the enzyme catechol-O-methyltransferase
Antiviral The hypericin to act effectively requires an intactmembrane or cell surface (viral envelope)
Bianchi et al., 1997; Bombardelli andMorazzoni, 1995; Yip et al., 1996; Degaret al., 1992; Bianchi et al., 1997;Takahashi et al., 1989
The mechanism of action includes the photo-activation of hypericinAction at the level of the anchor assembly or virusBinding of hypericin to the lipid membrane of thevirus by inhibition of viral fusion and syncytiumformationDirect action against the capsid of the virus byinhibiting mobilityInhibition of protein kinase C phosphorylation of thereceptor involved in CD4Inhibition of tyrosine kinase
Anticancer Molecule inhibition of nuclear factor κB, the switchcircuits of inflammation and inflammatory angiogenesis
Vandebogaerde and de Witte, 1995
Blocking of the endothelium migration in response toinflammatory cytokines
Vandebogaerde and de Witte, 1995;Thomas et al., 1992a, 1992b
Prevention of Alzheimer’sdisease
Hypericin may interfere with the processes ofpolymerization of beta-amyloid peptide responsiblefor the onset of Alzheimer’s disease
Griffith et al., 2010
Antibacterial Presence of substances with antimicrobial,antibacterial, and antifungal (essential oils,phloroglucinols, flavonoids, and tannins) activity
Saddiqe et al., 2010
Antigastritis and gastric ulcer Soothing and healing. Zdunić et al., 2009Topical Antibacterial properties Schempp et al., 1999
HYPERICUM PERFORATUM: PK, MOA, SAFETY, AND DDI
was ~100ng/ml (Biber et al., 1998) with a half-life of 9 h(Nangia et al., 2000) (Table 2).Although the poor pharmacokinetic profile of HP
extracts [i.e. low bioavailability (15–20%) and poorblood–brain barrier penetration] has been correlatedwith the 4- to 6-week treatment period typicallyrequired to achieve a therapeutic benefit in patients(Bennett et al., 1998), it should be noted that conventionalantidepressants with better pharmacokinetic profilesalso typically require a similar treatment period beforetherapeutic effects are seen (Woelk, 2000).Hypericum perforatum’s ability to act as a substrate of
both CYPs and P-gp has been widely confirmed in vitro(Perloff et al., 2001), in vivo (Imai et al., 2008), and inclinical studies (Xie et al., 2005). In the latter case, HPinduces the activity of several CYP isozymes includingCYP3A4, CYP2E1, and CYP2C19, thereby increasingthe metabolism of many drugs (Gurley et al., 2005;Wang et al., 2004). Moreover, HP’s effect upon CYP3A4has been studied in greater detail where HP administra-tion via the oral route affected midazolam metabolism
to a greater extent than via the intravenous route,which suggests that HP primarily acts via intestinal,and not hepatic, CYP3A4 (Wang et al., 2001; Dresseret al., 2003).
P-glycoprotein, one of the most clinically importanttransmembrane transporters in humans, is extensivelydistributed and expressed in the intestinal epithelium,hepatocytes, renal proximal tubular cells, adrenalgland, and capillary endothelial cells comprising theblood–brain barrier (Thiebaut et al., 1987), a specificlocalisation that suggests an active role in drug elimina-tion and absorption (Zhou, 2008). HP induces synthesisof P-gp in the intestines to reduce drug absorption(Perloff et al., 2001), and in kidneys, resulting inincreased drug excretion. The former effect has alsobeen reported in the gut of healthy volunteers(Hennessy et al., 2002) and may therefore reduce orincrease plasma concentrations of known P-gp sub-strates such as digoxin (Dürr et al., 2000), fexofenadine(Dresser et al., 2003; Xie et al., 2005), and talinolol(Schwarz et al., 2007).
Figure 1. Chemical structures of hypericin, pseudohypericin, andhyperforin. Structures of the main chemical constituents ofHypericum: the naphthodianthrone hypericin and pseudohypericinand phloroglucinol hyperforin.
E. RUSSO ET AL.
These HP effects on P-gp or CYP enzymes are typi-cally observed after treatment periods of at least 10 days(Wang et al., 2002), and although data following acute(1–3 days ) or shorter (i.e. 4–9 days ) treatment periodsare not available, no relevant clinical effects have beenreported (Rengelshausen et al., 2005). Furthermore, thedegree of CYP3A4 and P-gp induction is comparablebetween ethnic groups, specifically Caucasians, AfricanAmericans, Hispanics, Chinese, Indians, and Malays(Xie et al., 2005). Finally, hyperforin appears to be respon-sible for the increased expression of CYPs and P-gp(Will-Shahab et al., 2009). Indeed, hyperforin is a pow-erful inducer of CYP3A4 and P-gp (Zhou et al., 2007),and clinical results indicate that hyperforin contentdetermines the extent of HP–drug interactions becauseextracts containing little hyperforin exert only weakeffects on CYP and P-gp (Will-Shahab et al., 2009).
Table 2. Pharmacokinetics of hyperforin, hypericin, and pseudohyperic
In recent years, many studies have proven the efficacy ofsome HP extracts in the treatment of mild to moderatedepression, leading to its successful use as an antidepres-sant in both Europe and the USA (Kasper et al., 2006;Schrader, 2000; Linde et al., 1996; Linde and Knüppel,2005; Schrader et al., 1998; Woelk, 2000; Uebelhacket al., 2004; Kasper et al., 2008). The average daily dosetypically required to such effects is 900mg (range:600–1200mg ) of dry extract as three divided doses perday. Its efficacy and tolerability are well established withclinical studies demonstrating activity comparable withconventional antidepressants, while lacking major sideeffects. As described earlier, suspected HP-related ad-verse events are primarily limited to mild gastrointestinalor cutaneous reactions although the overall incidence ofsuch events is lower than side effects typically reportedfor tricyclic antidepressants (Kim et al., 1999) or selectiveserotonin reuptake inhibitors (SSRIs) (Lecrubier et al.,2002; Schrader, 2000; Woelk, 2000; Szegedi et al., 2005;Gastpar et al., 2006). In clinical studies, HP has showneffectiveness as an antidepressant that is higher thanplacebo in mild or moderate depression, and at leastone study has suggested that HP is superior to paroxetinein the treatment of moderate to severe depression(Szegedi et al., 2005). More than 50 randomised con-trolled trials and more than 15 larger observationalstudies have now investigated the effectiveness of HPextracts in the acute treatment of depressive disorders.Results of the first trial became available in 1979(Hoffmann and Kühl, 1979), and until the mid-1990s,about 25 trials were published. Furthermore, clinicalstudies have compared the effectiveness of HP with thatof tricyclic antidepressants (Linde et al., 2008; Schulz,2006) and found their effects to be largely comparable.
A recent, meta-analysis of randomised controlledtrials reported similar efficacy for the acute use of HPextracts as with SSRIs (Rahimi et al., 2009) although nocomparative studies of efficacy associated with medium-term and long-term use exist, making it impossible toascertain HP’s effectiveness as a maintenance treatmentfor patients with recurrent depression or other distur-bances (dysthymia and bipolar disorder). Also, identifica-tion of the optimal therapeutic dose of HP remainsdifficult because different concentrations have been usedin clinical trials, but none have been specifically under-taken to determine either a minimum effective or optimaldose. Broadly, the majority of studies have used HPextracts standardised to 0.2–0.3% hypericin with dosesranging from 400- to 900-mg HP extract daily. Although
several large studies have shown that HP can be an effec-tive treatment for major depression, others have foundcontrary results (Montgomery et al., 2000; Shelton et al.,2001; Hypericum Depression Trial Study Group, 2002).Finally, more limited research suggests that HP has
antimicrobial properties that may be of use in thetreatment of burns and wounds (Öztürk et al., 2006;Rao et al., 1991), whereas other preclinical in vitro andin vivo studies have suggested that HP may hold valuein the treatment of other ailments, including cancer,inflammatory disorders, and bacterial and viral diseases,as well as potential uses as an antioxidant andneuroprotective agent (Klemow et al., 2011). However,the extent to which these suggestions might translateto clinical practice remains unrealised.
SAFETY OF HYPERICUM PERFORATUM
Although HP extracts appear to be well tolerated, themost frequently reported side effects are nausea, rash,fatigue, restlessness, and photosensitivity (Table 3), whichhas been largely attributed to naphthodianthrones(hypericin and pseudohypericin) (Rodríguez-Landa andContreras, 2003; Schulz et al., 2006) and typicallymanifests at higher-than-recommended doses. Althoughsevere phototoxic reactions seem to be very rare events(only two cases of severe photo-allergic reactions follow-ing ingestion of HP preparations have been reported inthe literature; Schulz, 2006), patients should be informedthat HP extracts, like some SSRIs, can increase light sen-sitivity (Doffoel-Hantz et al., 2009). In an open study of3250 patients, the most commonly reported side effectswere gastrointestinal symptoms (0.6%), allergic reactions(0.5%), and fatigue (0.4%) (Woelk et al., 1994), whereas,in a meta-analysis of 23 studies, 19.8% of patients usingHP preparations reported side effects, as compared with35.9% of subjects using standard antidepressant medica-tions with 4% of patients in the HP group dropping outin comparison with 7.7% receiving standard antidepres-sants (De Smet and Nolen, 1996).The safety of using HP during pregnancy is important,
not least because women in their reproductive years arefrequent users of natural health products (Eisenberget al., 1998; Fugh-Berman and Kronenberg, 2003) andmay develop depression during pregnancy (Bennettet al., 2004). There are very limited data to support thesafety of HP use during pregnancy or breastfeeding;Lee et al. (2003) compared 30 breastfeeding womentaking different HP preparations for postnatal depression
Table 3. Overview of Hypericum perforatum extract-relatedadverse drugs reactions
Adverse drugs reactions References
Nausea, rash, asthenia,and restlessness
Schrader, 2000; Woelk, 2000; Rodríguez-Landa and Contreras, 2003; Woelk et al.,1994
Photosensitivity Schulz, 2006; Rodríguez-Landa andContreras, 2003; Golsch et al., 1997;Bove, 1998; Nierenberg, et al., 1999;Moses and Mallinger, 2000
Serotonin syndrome Evans, 2008; Bonetto et al., 2007
with other breastfeeding mothers not taking the com-pound and reported several adverse events in infantsnursed by mothers taking HP (two cases of colic, two ofdrowsiness, and one of lethargy).
A prospective, observational, controlled cohort studycompared 54 women exposed to HP during pregnancywith 108 others who were also pregnant and eithertaking conventional antidepressants (n= 54) or wereotherwise healthy (n= 54). Results showed no signifi-cant difference (p= 0.26) in rates of major postnatalmalformations across groups (5%, 4%, and 0%), andthe authors noted that these rates are comparable withthe risk expected in the general population (Morettiet al., 2009). A small number of animal studies haveshown that HP does not affect cognitive development,long-term growth, or physical maturation and causesno long-term behavioural deficits. However, otheranimal studies have reported lower birth weights inoffspring when HP was consumed during pregnancyand that HP may increase uterine tone (Rayburn et al.,2000, 2001a, 2001b; Dugoua et al., 2006). Furthermore,Gregoretti et al. (2004) demonstrated that chronic HPtreatment during pregnancy or lactation can be respon-sible for histological alterations in the liver and kidneyof rats.
Other HP side effects include confusion, restlessness,lethargy, and dryness of the mouth (Klemow et al.,2011), and in some cases, HP use has been associatedwith psychotic events (Shimizu et al., 2004; Stevinsonand Ernst, 2004).
HYPERICUM PERFORATUM–DRUGINTERACTIONS
Central nervous system drugs
Major drug classes with central nervous system activityinclude antidepressants, antipsychotics, antiepileptics,and anxiolytics but also anaesthetics and analgesics.They act differently to exert their therapeutic effectbut can be grouped by virtue of a common metabolicpathway involving CYP. Co-administration of HP withthese substances induces either reduced plasma concen-trations due to enzyme induction or a summation ofeffects, depending on the case (Table 4).
A primary concern associated with the use of HParises via its putative action as an SSRI leading to aconsequential risk of serotonin syndrome (Lantz et al.,1999), a potentially life-threatening condition arisingfrom excessive serotonergic stimulation. Serotonin syn-drome is characterised by at least three of the following:confusion, agitation, hyperreflexia, diaphoresis, shiveringor tremor, nausea, diarrhoea, lack of coordination, fever,coma, flushing, or rhabdomyolysis (Cookson, 1993). It isusually caused by use of therapeutic drugs (e.g. SSRIs),drug–drug interactions, intentional self-poisoning, ordeliberate poisoning (Boyer and Shannon, 2005; Mathewet al., 1996). In fact, many drug combinations have beenassociated with serotonin syndrome; for example, aclinical study reported seizures in a patient with serotoninsyndrome symptoms followed by acute rhabdomyolysis,a condition apparently precipitated by concurrenttriptan use with long-term fluoxetine and HP treatment
cytochrome and P-gpHe et al., 2012; Hu et al., 2005
Tacrolimus Organ rejection Mai et al., 2003Hypoglycaemic agentsGliclazide Decreased plasma concentration Induction enzymes
cytochrome and P-gpIzzo and Ernst, 2009
Tolbutamide Di et al., 2008
AUC, area under the curve; HP, Hypericum perforatum; LDL, low-density lipoprotein; P-gp, P-glycoprotein.
HYPERICUM PERFORATUM: PK, MOA, SAFETY, AND DDI
(Evans, 2008). Therefore, triptan use with concurrent flu-oxetine and HP may be inappropriate (Bonetto et al.,2007). Moreover, HP and SSRIs or buspirone orbupropion can exert additive effects on serotonin reuptakeinhibition that are responsible for serotonin syndrome(Borrelli and Izzo, 2009; Caraci et al., 2011).Additional potential pharmacokinetic interactions are
associated with hypericin’s induction of CYP3A4 andCYP2C19 and include reductions of the AUC and half-life and a significant increase of oral clearance of benzodi-azepines (alprazolam and midazolam) (Hall et al., 2003;Markowitz et al., 2003) in addition to reducing the AUCof amitriptyline and nortriptyline. Furthermore, theinduction of CYP2C19 is responsible for increasedurinary excretion of phenytoin metabolites (Borrelli andIzzo, 2009) and decreased plasma concentration ofzolpidem, probably by enhancing CYP3A4 activity (Hojoet al., 2011), whereas induction of CYP1A2 and CYP3A4was responsible for HP-induced decreases in clozapine’sAUC (Van Strater and Bogers, 2012). With respect toanticonvulsant drug–HP interactions, no significant influ-ence of HP on the pharmacokinetics of carbamazepine,sodium valproate, or phenobarbital have been reported(Rahimi and Abdollahi, 2012; Dasgupta et al., 2006).However, although HP modulation of CYP enzymes
has been quite well described, the mechanism underly-ing HP-induced delay in onset of the effects of thegeneral anaesthetics fentanyl, propofol, and sevofluranedescribed by Borrelli and Izzo (2009) has not beenelucidated. It should however be noted that pharmaco-kinetic changes reported for HP cannot be extrapolatedto clinically relevant events although the potential forclinically relevant interactions is greatest for drugsexhibiting very narrow therapeutic indices.
Bronchodilators
The only reported interaction for this drug category iswith theophylline where HP significantly reduces AUCand blood concentrations through CYP3A4 inhibitionto cause a loss of asthma control (Chen et al., 2012)(Table 4). A single case of decreased plasma levels oftheophylline following HP treatment (300mg daily) hasbeen reported (Nebel et al., 1999) and necessitated anincreased dosage of theophylline to restore therapeuticeffects. However, this remains a single case because acontrolled population study demonstrated that HP
administration (300mg/day) for 15 days did not affectplasma or urine levels of theophylline (Morimoto et al.,2004). Therefore, there is limited evidence to supportwidespread concern about this interaction althoughmonitoring of theophylline dose and blood levels inpatients using HP may be necessary if poor symptomcontrol is evident in individual patients.
Cardiovascular drugs
Oral anticoagulants. Oral anticoagulants are vitamin Kantagonists and act in the liver to inhibit synthesis offactors II, VII, IX, and X of the coagulation and theanticoagulant proteins C and S by competitive inhibitionof the enzyme epoxide reductase. Warfarin is the mostwidely used molecule of this class, the metabolism ofthe two enantiomers of which is undertaken by differentcytochromes, whose activity is susceptible to modulationby concomitant intake of other cytochrome substrates.Thus, R-warfarin is mainly metabolised by CYP1A2and CYP3A4 and S-warfarin, the more potent form,predominantly by CYP2C19A.
A clinical trial showed that HP induces the apparentclearance of both S-warfarin and R-warfarin, which, inturn, resulted in a significant reduction in racemicwarfarin’s pharmacological effect (Jiang et al., 2004).Similarly, another trial revealed HP-induced decreasesin plasma levels of phenprocoumon (a coumarinic anti-coagulant chemically related to warfarin) (Chen et al.,2012) (Table 4). Together, these results provide a basisto explain a number of case reports (~29 as of 2005) ofincreased prothrombin time or corresponding decreasesin international normalised ratio associated with warfarin(Yue et al., 2000) or phenprocoumon (Bon et al., 1999)with HP use. Despite these sometimes significant changesin pharmacokinetic parameters, no cases of bleeding epi-sodes or thrombotic events attributable to concomitantHP use have been reported (Schulz and Johne, 2005).
Gröning et al. (2003) have investigated the physical–chemical interactions between HP extracts and severaldrugs, more precisely, the formation of nanoparticles,microparticles, and precipitates in aqueous drug-freeand drug-containing preparations of HP. In aqueousinfusions of HP, only small amounts of nanoparticlesand microparticles were observed using photon correla-tion spectroscopy and scanning electron microscopy.Warfarin has a negligible effect on the particle formation
Phytother. Res. (2013)
E. RUSSO ET AL.
in aqueous infusions. However, in further studies withHPdry extracts reconstituted in water, nanoparticles and pre-cipitates are already formed in other drug-free prepara-tions. In this case, the amount of free warfarin in thesolution is maximally reduced by 36.6%. The authorssuggested that the loss of anticoagulant effect describedin literature may partly be caused by particle formationduring drug administration (Gröning et al., 2003).
Calcium channel blockers. Nifedipine, a calcium channelantagonist, is primarily metabolised by CYP3A4 todehydronifedipine. As such, nifedipine is often used asa probe drug for determining CYP3A4-mediateddrug–drug interactions in human studies. A rapid andsensitive liquid chromatography/tandem mass spec-trometry method was developed and validated to deter-mine nifedipine and dehydronifedipine simultaneouslyin human plasma. This method has been successfullyused by Wang et al. (2007) to study nifedipine pharma-cokinetic interactions with HP in healthy volunteerswhere HP was shown to induce nifedipine metabolismto increase plasma concentrations of dehydronifedipine(Wang et al., 2007). HP also interacts with verapamil toreduce its bioavailability by induction of first-passCYP3A4 metabolism, most likely in the gut (Tannergrenet al., 2004) (Table 4).
Cardiac inotropic drugs. Digoxin is a digitalis drug usedto increase the force of contraction of both atrial andventricular myocardial fibres (positive inotropic effect).Drug interaction studies with digoxin are particularlyimportant because of its low therapeutic index. It hasbeen shown that chronic HP use lowers the bioavailabilityof digoxin, potentially via reduced intestinal absorptionarising from induction of the multidrug resistance trans-porter, P-gp. Actually, the concurrent action of intestinalCYP3A4 and P-gp creates an absorption barrier, whichinfluences the oral bioavailability of many medications(Wacher et al., 1996; Watkins, 1997). Digoxin is a P-gpsubstrate and is largely unmetabolised in humans; thus,after 10days of HP treatment, oral digoxin exhibited a25% reduction of both plasmaAUC andmaximum bloodconcentration (Cmax) (Johne et al., 1999; Di et al., 2008).Moreover, consistent with these results, two trials havealso shown decreased plasma digoxin concentrationsfollowing 10days of HP administration (Johne et al.,1999; Mueller et al., 2004). Consistent with intestinalinduction of P-gp, this interaction was characterised by areduction in AUC0–24 and Cmax, which led to a reductionin Ctrough, whereas in the parallel study of Mueller et al.(2004), a 25% decrease in steady-state digoxin concentra-tion was observed in a group of healthy volunteers.Conversely, in the same study, administration of othercrude preparations (teas, oil, and alcohol extract) pro-duced no (or only marginal) effects on digoxin plasmalevels. Thus, the extent of HP–digoxin interactions varybetween HP preparations and doses but does appearparticularly well correlated with hyperforin levels(Mueller et al., 2004) (Table 4). Although the precedingresults suggest that HP-mediated decreases in digoxinlevels are clinically relevant, no cases of therapeuticinteractions between HP and digoxin have been reportedto date.
Hypocholesterolaemic drugs. ‘Statins’ or inhibitors of3-hydroxy-3-methylglutaryl coenzyme A reductase, the
key enzyme in the biosynthetic pathway of cholesterol,are the drugs of choice for the treatment ofhypercholesterolaemia and can reduce the risk ofcardiovascular morbidity and mortality (ScandinavianSimvastatin Survival Study Group, 1994; West of ScotlandCoronary Prevention Study Group, 1998) in subjects withcardiovascular disease. Statins are hepatically metabolisedthrough catalysis induced by CYP2C9 (fluvastatin) orCYP3A4 (simvastatin, lovastatin, and atorvastatin)(Shitara and Sugiyama, 2006). Furthermore, atorvastatinmight inhibit P-gp and may also be a substrate for thistransporter (Holtzman et al., 2006). With regard to HP,controlled clinical studies revealed that mean low-densitylipoprotein cholesterol level and total cholesterol are sig-nificantly higher after 4weeks of treatment with productscontaining HP despite the use of statins (atorvastatin andsimvastatin) (Andrén et al., 2007; Eggertsen et al., 2007)(Table 4). HP lowers simvastatin plasma levels, whereasno interaction with pravastatin was observed (Sugimotoet al., 2001). Furthermore, in patients with hypercholester-olemia receiving simvastatin, HP can increase low-densitylipoprotein levels (Eggertsen et al., 2007) (Table 4).Moreover, it is very likely that products containing HPmay interact with atorvastatin (Andrén et al., 2007).
Drugs acting on the gastrointestinal tract
Proton pump inhibitors (PPIs) are hepatically metabolisedby two isozymes of CYP (CYP2C19 and CYP3A4).Pantoprazole is also metabolised by a cytosolicsulfotransferase, esomeprazole primarily by CYP2C19,and omeprazole by CYP3A4. In particular, caution shouldbe exercised when taking omeprazole and esomeprazolewith HP as reduced plasma concentrations of PPIs havebeen reported (Wang et al., 2004).
Although no single scientific study yet publisheddescribes interactions between HP and antidiarrhoealmedications, Khawaja et al. (1999) documented a briefepisode of acute delirium, possibly induced by exposureto HP, valerian root, and loperamide. It was suggestedthat the observed delirium was related to the concomi-tant use of these medications, although the mechanismwas not elucidated (Khawaja et al., 1999). Loperamidealone can cause delirium, but it remains possible thatHP and/or valerian contributed to the precipitation ofthis event (Schwartz and Rodrigues, 1991) (Table 4).
Oral contraceptives
Clinical studies have demonstrated a higher incidence ofintracyclic bleeding episodes after co-administration ofHP and oral contraceptives (Hall et al., 2003; Murphyet al., 2005). The intermenstrual bleeding is believed toarise from HP-induced reductions in plasma concentra-tions of oral contraceptive tablet components (Table 4).Furthermore, such bleeding irregularities could adverselyaffect compliancewith oral contraceptive use and, togetherwith HP-induced decreases in serum 3-ketodesogestrelconcentrations, enhance the risk of unintended pregnan-cies (Will-Shahab et al., 2009). Conversely, from thereported extensive use of a leading European HP extractby women of child-bearing age (~4 million between 1991and 1999), eight reports of interim bleeding equate to anincidence of approximately 1 report per 500 000 women
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HYPERICUM PERFORATUM: PK, MOA, SAFETY, AND DDI
treated, which is an incidence lower than that of interimbleeding associated with oral contraceptive use alone(Rosenberg et al., 1996).
Antiinflammatory drugs, corticosteroids, and opioids
Among the non-steroidal antiinflammatory drugs,ibuprofen interacts with HP; increased P-gp expressionreduces plasma levels of the drug and, consequently,decreases its effects (Bell et al., 2007a) (Table 4). TheCYP3A4 pathway also mediates the metabolism ofcorticosteroids: prednisone, prednisolone, dexamethasone,and budesonide; HP co-administration reduces their AUC(Bell et al., 2007b).The induction of CYP3A4 and CYP2D2 by HP also
reduces the plasma concentration of several opioids suchasoxycodone, dextromethorphan, andpethidine (Table4)(Dostalek et al., 2005; Nieminen et al., 2010); interactionsthat may be of clinical significance when consideringpatients with chronic pain (Nieminen et al., 2010).
A number of clinically significant interactions of HPwith antibacterial, antifungal, and antiviral drugs havebeen identified (Di et al., 2008), and thus, concomitantadministration of HP should be avoided in order toreduce treatment failures, particularly in high-risk cases.Antimicrobial drugs are substrates of CYP3A4, and it isknown that HP-mediated induction of CYP3A4 reducesthe AUC of voriconazole, erythromycin, and indinavir(Borrelli and Izzo, 2009; Chen et al., 2012) (Table 4).
Antineoplastic drugs
Hypericum perforatum extracts, via induction of bothCYP3A4 and P-gp, may reduce plasma concentrationsof several antineoplastic agents (e.g. imatinib, irinotecan,and docetaxel) and hence their clinical efficacy (Izzo andErnst, 2009) (Table 4). Specifically, an unblinded,randomised crossover study showed that patients treatedwith irinotecan should abstain from taking HP becauseplasma levels of this drug were dramatically reduced, aninteraction with the potential to exert a deleteriousimpact on treatment outcome (Mathijssen et al., 2002).Moreover, two trials found increased imatinib clearancefollowing HP administration, confirming that the HP co-administration can affect the therapeutic action of theantineoplastic drug (Frye et al., 2004; Smith et al., 2004).
Immunosuppressant drugs
A 2003 study confirmed previous clinical trials and casereports describing interaction between HP and immuno-suppressive drugs (Alscher and Klotz, 2003) where HPsignificantly reduced both AUC and plasma concentra-tions of cyclosporine and tacrolimus (Table 4) (Hu et al.,2005; Chen et al., 2012). An important consequence ofthese interactions may be the risk of organ rejection(Mai et al., 2003).
Clinical trials indicate that HP, via CYP and/or P-gpinduction, can reduce the plasma concentrations (and/orincrease the clearance) of gliclazide (Izzo and Ernst,2009). Although HP does not alter the pharmacokineticsof tolbutamide, it does increase the incidence ofhypoglycaemia (Zhou et al., 2004), with a more recentclinical study demonstrating that both pharmacokineticand pharmacodynamic components may play a role inthese interactions (Table 4) (Di et al., 2008).
DISCUSSION
Here, we have summarised the safety and efficacy of HPand classified the potential clinical effects of known orevidence-based potential interactions between conven-tional drugs and HP. HP is one of the oldest and best-investigated medicinal herbs, and substantial evidencesupports its effectiveness in the treatment of variousforms of depression and anxiety (Rahimi and Abdollahi,2012) although the most clearly relevant safety issue withHP extracts lies with HP–drug interactions. Notably,extracts containing low or negligible amounts ofhyperforin can be effective in the treatment of depressionbut lack interactive potential (Mueller et al., 2009). HPextracts are potent activators of the enzymes CYP3A4and CYPC19 (Hemeryck and Belpaire, 2002), enzymesthat play a relevant role in the metabolism of many drugs.Furthermore, HP extracts also increase the activity ofP-gp, which is responsible for increased excretion ofdrugs. Thus, pharmacokinetic interactions can occurwhen HP is combined with drugs that are metabolisedthrough CYP3A4, CYP2C19, and/or are P-gp substrates(Chen et al., 2011). Pharmacodynamic interactions canoccur when HP is combined with drugs that increase theconcentration of 5-hydroxytryptamine in the brain (Chenet al., 2011). HP interactions include reduced bloodconcentration of anticoagulants, cyclosporine, gastroin-testinal drugs, and antineoplastic drugs (e.g. imatinib);serotonin syndrome; or lethargy when HP was given con-comitantly with SSRIs. However, many others that arepredictable might have not been reported or studied.More generally, HP interaction with drugs metabolisedby CYPs might be easily controlled, whereas the role ofP-gp appears to be more complex (Ott et al., 2010).
CONCLUSIONS
Herb–drug interactions associated with HP have beeninvestigated to a greater extent than that for any otherbotanical. The fact that HP affects CYP and P-gp, theprimary substrates associated with conventional drugmetabolism, raises significant concerns for HP–druginteractions. Despite reports of changes in pharmacoki-netics of a variety of conventional medications and thewidespread use of HP worldwide, the incidence ofclinically relevant interactions based on clinical studies,case reports, and pharmacovigilance data remains verysmall. The greatest risk for HP–drug interactions is fordrugs that have a narrow therapeutic and safety index.Additionally, aside from the potential of interactions,
there is a very low incidence of adverse effects with HPuse. The low incidence of side effects and the low cost ofHP represent an interesting therapeutic alternative tosynthetic antidepressants when used alone. There isgood evidence that HP and preparations with lowhyperforin content can be effective as monotherapiesfor the treatment of mild to moderate depression(Mueller et al., 2009). However, potential herb–drug
interactions should be considered and monitored, andtherapies adjusted as necessary.
Conflict of Interest
The authors have declared that there is no conflict of interest.
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