REVIEW ARTICLE published: 30 April 2012 doi: 10.3389/fphar.2012.00069 An overview of the evidence and mechanisms of herb–drug interactions

Pius S. Fasinu 1, Patrick J. Bouic 2,3 and Bernd Rosenkranz 1*

1 Division of Pharmacology, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa 2 Division of Medical Microbiology, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa 3 Synexa Life Sciences, Montague Gardens, Cape Town, South Africa

Edited by: Despite the lack of sufficient information on the safety of herbal products, their use as Javed S. Shaikh, Cardiff Research alternative and/or complementary medicine is globally popular. There is also an increasing Consortium: A CAPITA Group Plc Company, India interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is Reviewed by: the concurrent consumption of herbal products and conventional drugs. Herb–drug inter- Sirajudheen Anwar, University of action (HDI) is the single most important clinical consequence of this practice. Using a Messina, Italy structured assessment procedure, the evidence of HDI presents with varying degree of Domenico Criscuolo, Genovax, Italy clinical significance. While the potential for HDI for a number of herbal products is inferred Roger Verbeeck, Université Catholique de Louvain, Belgium from non-human studies, certain HDIs are well established through human studies and *Correspondence: documented case reports. Various mechanisms of pharmacokinetic HDI have been iden- Bernd Rosenkranz, Division of tified and include the alteration in the gastrointestinal functions with consequent effects Pharmacology, Department of on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; Medicine, University of Stellenbosch, and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic phar- PO Box 19063, Tygerberg, Cape Town 7505, South Africa. macologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. e-mail: [email protected] The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications.

Keywords: Herb–drug interaction, traditional medicine, phytochemicals, transport proteins, cytochrome P450

INTRODUCTION Canada (Calixto, 2000), Australia (Bensoussan et al., 2004), as well There is increasing consumptions of medicinal herbs and herbal as Europe where the highest sales of herbal products have been products globally, cutting across social and racial classes, as it reported in Germany and France (Capasso et al., 2003). In Africa, is observed both in developing and developed countries (Cheng there is continuous addition to the list of medicinal herbs while et al., 2002; Bodeker, 2007; Mitra, 2007). Medicinal plants were the consumption rate is also increasing. Between 60 and 85% native major agents for primary health care for many centuries before Africans use herbal medicine usually in combination (Van Wyk the advent of modern medicine (Sheeja et al., 2006). Their use et al., 2009). however declined in most developed western countries during The indications for herbal remedies are diverse as they are the last century’s industrialization and urbanization (Ogbonnia employed in the treatment of a wide range of diseases (Ernst, et al., 2008). In the past two decades however a new resurgence 2005). Studies have shown that 67% of women use herbs for in medicinal plants consumption was observed. According to the perimenopausal symptoms, 45% use it in pregnancy, and more WHO, about 70% of the world population currently uses medic- than 45% parents give herbal medications to their children for inal herbs as complementary or alternative medicine (Wills et al., various medical conditions (Ernst, 2004). Regulations in most 2000). It is estimated that over 40% of the adult American popula- countries do not require the demonstration of therapeutic effi- tion consume herbal products for one medical reason or the other cacy, safety, or quality on the part of herbal remedies as most of (Tachjian et al.,2010). A recent study involving 2055 patients in the them are promoted as natural and harmless (Homsy et al., 2004; US also reveals that the consumption pattern of traditional med- Routledge, 2008). It is pertinent however, that herbs are not free ications has no significant gender or social difference (Kessler et al., from side effects as some have been shown to be toxic (Déciga- 2001). Consumption rate has also been particularly exponential in Campos et al., 2007; Patel et al., 2011). Recent study has shown

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habitual pattern of concomitant consumption of herbal and pre- sesquiterpenes,steroids,carotenoids,saponins,and iridoids),alka- scription medication. Kaufman et al. (2002) reported that 14–16% loids, peptides, polysaccharides (such as gums and mucilages), of American adult population consume herbal supplements often resins, and essential oils which often contain some of the afore- concomitantly with prescribed medications. Also, 49.4% of Israeli mentioned classes of phytochemicals (Wills et al., 2000; Wang consumers of herbal remedies use them with prescription drugs et al., 2008). This complexity increases the risk of clinical drug (Giveon et al., 2004). This is significant bearing in mind that less interactions. than 40% of patients disclose their herbal supplement usage to their health care providers coupled with the fact that many physi- AIM, SEARCH STRATEGY, AND SELECTION CRITERIA cians are unaware of the potential risks of herb–drug interactions The current review was therefore aimed at providing an overview (HDI; Klepser et al., 2000). of known and recently reported HDI with interest in the evi- HDI is one of the most important clinical concerns in the dence available and the mechanism thereof. The review was concomitant consumption of herbs and prescription drugs. The systematically conducted by searching the databases of MED- necessity of polypharmacy in the management of most diseases LINE, PUBMED, EMBASE, and COCHRAINE libraries for orig- further increases the risk of HDI in patients. The ability of inal researches, and case reports on HDI using the following intestinal and hepatic CYP to metabolize numerous structurally search terms or combinations thereof: “drug–herb,”“herb–drug,” unrelated compounds, apart from being responsible for the poor “interaction,” “cytochrome P450,” “plant,” “extract,” “medicinal,” oral bioavailability of numerous drugs is responsible for the large “concomitant administration,”“herbal and orthodox medicines.” number of documented drug–drug and drug–food interactions Relevant search terms were employed to accommodate the vari- (Quintieri et al., 2008). This is more so, considering that oral drug ous individual medicinal herbs employed in Africa, America, Asia, delivery is the most employed in the management of most disease Europe, and Australia. The reported interactions and their mech- conditions in which case, drug interaction alters both bioavailabil- anisms, with orthodox medications were searched and collated. ity and pharmacokinetic disposition of the drug. This alteration Searches were not limited by date or place of publications but to and the resulting poor control of plasma drug concentrations publications available in English language. would particularly be of concern for drugs that have a narrow therapeutic window or a precipitous dose–effect profile (Aungst, RESULTS 2000; Perucca, 2006). The risk of pharmacokinetic drug interac- CLINICAL PRESENTATION OF HERB–DRUG INTERACTIONS tion poses two major extremity challenges – pharmacotoxicity and Clinical presentations of HDI vary widely depending on the herbs treatment failure. The former can result from the inhibition of the and the drugs concerned. Typical clinical presentation of HDI metabolic enzymes responsible for the metabolism and clearance include the potentiation of the effects of oral corticosteroids in the of the drugs while the latter may be the consequence of enzymatic presence of liquorice (Glycyrrhiza glabra; Liao et al., 2010); poten- induction leading to faster drug metabolism. This is in addition tiation of warfarin effects with resultant bleeding in the presence to the intrinsic pharmacodynamic actions of the herbal products of garlic (Allium sativum; Borrelli et al., 2007), dong quai (Angel- themselves which may include potentiating, additive, antagonism, ica sinensis; Nutescu et al., 2006), or danshen (Salvia miltiorrhiza; or neutralization effects. Chan, 2001); decreased blood levels of nevirapine, amitriptyline, Until recently,HDI was often unsuspected by physicians for sev- nifedipine, statins, digoxin, theophylline, cyclosporine, midazo- eral reasons. Most trained physicians lack adequate knowledge on lam, and steroids in patients concurrently consuming St John’s herbal drugs and their potentials for drug interactions (Clement wort (SJW; Hypericum perforatum; De Maat et al., 2001; Hender- et al., 2005; Ozcakir et al., 2007; Fakeye and Onyemadu, 2008); son et al., 2002; Johne et al., 2002; Mannel, 2004; Borrelli and herbal products also vary considerably in compositions depending Izzo, 2009), decreased oral bioavailability of prednisolone in the on the source and package (Liang et al., 2004; Sousa et al., 2011); presence of the Chinese herbal product xiao-chai-hu tang (sho- most patients do not consider it necessary to disclose their herbal saiko-to; Fugh-Berman, 2000); ginseng (Panax ginseng)-induced consumptions to physicians who themselves hardly inquire such mania in patients on antidepressants (Engelberg et al., 2001); (Cassidy,2003; Howell et al.,2006; Chao et al.,2008; Kennedy et al., production of extrapyramidal effects as a result of the combi- 2008). Further challenges with herbal medications include scien- nation of neuroleptic drugs with betel nut (Areca catechu; Huang tific misidentification, product contamination and adulteration, et al., 2003; Coppola and Mondola, 2012); increased blood pres- mislabeling, active ingredient instability, variability in collection sure induced by tricyclic antidepressant-yohimbe (Pausinystalia procedures, and failure of disclosure on the part of patients (Boul- yohimbe) combination (Tam et al., 2001), increased phenytoin lata and Nace, 2000). A fairly recent systematic review by Izzo clearance and frequent seizures when combined with Ayurvedic and Ernst (2009) on the interactions between medicinal herbs and syrup shankhapushpi (Patsalos and Perucca, 2003), among other prescribed medications provide some more details on these. clinical manifestations. These clinical presentations depend on the Herbal products are made of complex mixture of phar- mechanism of HDI. macologically active phytochemicals (Mok and Chau, 2006), most of which are secondary metabolites generated through EVIDENCE-BASED HDI STUDIES AND CLINICAL RELEVANCE the shikimate, acetate–malonate, and acetate–mevalonate path- Herb–drug interactions have been reported through various study ways. These constituents include phenolics (such as tannins, techniques. While these reports usually give evidence of potential lignins, quinolones, and salicylates), phenolic glycosides (such as interactions, the level of evidence varies often failing to predict flavonoids, cyanogens, and glucosinolates), terpenoids (such as the magnitude or clinical significance of such HDI. Apart from

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the specific limitations attributable to study methods employed, (Izzo, 2005). The major underlying mechanism of pharmacoki- major draw-back in deducting relevant conclusions from reported netic HDI, like drug–drug interaction, is either the induction or HDI include misidentification and poor characterization of spec- inhibition of intestinal and hepatic metabolic enzymes particu- imen, presence and nature of adulterants (some of which may be larly the CYP enzyme family. Additionally, similar effect on drug allergens), variations in study methodologies including extraction transporters and efflux proteins particularly the p-glycoproteins in procedures, source location of herbs involved, seasonal variation the intestines is responsible in most other cases (Meijerman et al., in the phytochemical composition of herbal materials, under- 2006; Nowack, 2008; Farkas et al., 2010). The pre-systemic activ- reporting and genetic factors involved in drug absorption, metab- ity of CYP and efflux proteins often influence oral bioavailability, olism, and dynamics. Table 1 provides some limitations of the thus the modulating activity of co-administered herbal products study methods. has been shown to result in pronounced reduction or increase in Recently, structured assessment procedures are emerging in an the blood levels of the affected drugs (Brown et al., 2008). attempt to provide levels of evidence for drug interactions. In Potential for in vivo drug interactions are often inferred from addition to evidence of interaction, such assessment take into con- in vitro studies with liver enzymes. The correlation of in vitro sideration clinical relevance of the potential adverse event resulting results with in vivo behavior has yielded reliable results in cer- from the interaction, the modification- and patient-specific risk tain cases in terms of in vivo predictability although the extent factors, and disease conditions for which the interaction is impor- of clinical significant is poorly inferable (Rostami-Hodjegan and tant. Van Roon et al. (2005) developed a system of hierarchical Tucker, 2007; Iwamoto et al., 2008; Xu et al., 2009; Umehara and evidence-based structured assessment procedure of drug–drug Camenisch, 2011). Thus most of the well established HDIs, as interaction. This can be applicable to HDI. This method particu- will be seen in subsequent sections, were initially demonstrated larly allows the extraction of HDIs that have been well established through in vitro studies. and those that are merely inferred from certain phytochemical The interaction of herbal products with hepatic enzymes can characteristics. A modified form of this method as presented in also result in pharmacodynamic effects (van den Bout-van den Table 2 is applied in this paper to provide the nature and level of Beukel et al., 2008; Nivitabishekam et al., 2009; Asdaq and Inam- evidence for the HDIs mentioned. dar, 2010; Dasgupta et al., 2010; Kim et al., 2010a.) Specific liver injury inducible by phytochemical agents includes elevation in MECHANISMS OF HERB–DRUG INTERACTIONS transaminases (Zhu et al., 2004; Saleem et al., 2010), acute and The overlapping substrate specificity in the biotransformational chronic hepatitis (Stedman, 2002; Pierard et al., 2009), liver fail- pathways of the physiologic systems is seen as the major reason for ure (Durazo et al., 2004), veno-occlusive disorders (DeLeve et al., drug–drug, food–drug, and HDI (Marchetti et al., 2007). The abil- 2002), liver cirrhosis (Lewis et al., 2006), fibrosis (Chitturi and ity of different chemical moieties to interact with receptor sites and Farrell, 2000), cholestasis (Chitturi and Farrell, 2008), zonal or alter physiological environment can explain pharmacodynamic diffusive hepatic necrosis (Savvidou et al., 2007), and steato- drug interactions while pharmacokinetic interactions arise from sis (Wang et al., 2009). Mechanism of liver injury may include altered absorption, interference in distribution pattern as well as bioactivation of CYP, oxidative stress, mitochondrial injury, and changes and competition in the metabolic and excretory pathways apoptosis (Cullen, 2005).

Table 1 | Comparison of study methods available for HDI.

Report/study method Comments Advantages Limitations to clinical inferences

In vitro studies Deliberate investigations employing Provide information on potential Variations in experimental vs clinical concen- metabolic enzymes, tissues, or HDI, easy to perform, good for high trations; other in vivo phenomena like protein organs, e.g., CYP-transfected cell throughput screenings; Compared binding and bioavailability are not accounted lines, hepatic subcellular fractions, to in vivo animal studies, results are for; poor reproducibility of results; poor corre- liver slices, intestinal tissues closer to human if human lation to clinical situation liver-based technologies are employed In vivo studies Involves metabolic studies in Concentration and bioavailability of Results are often difficult to interpret due to mammals active components are taken into species variation; use of disproportionate and consideration non-physiologic dosages Case reports Patients diagnosed after history Ideal in providing information on HDI Hardly discovered by physicians; infrequent taking, from HDI with poor statistical values in relation to each medicinal herbs; under-reporting Human studies Involves the use of human subjects The ideal study, providing directly Expensive; too stringent ethical considera- extrapolative data on interactions tions; most subjects are healthy leaving out the effects of pathologies on drug metabo- lism; genetic variation in enzyme activity; poor representative population

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Table 2 | Quality of HDI evidence for clinical risk assessment.

Level Description of evidence

1 Published theoretical proof or expert opinion on the possibility of HDI due to certain factors including the presence of known interacting phytochemicals in the herbs, structure activity relationship 2 Pharmacodynamic and/or pharmacokinetic animal studies; in vitro studies with a limited predictive value for human in vivo situation 3 Well documented, published case reports with the absence of other explaining factors 4 Controlled, published interaction studies in patients or healthy volunteers with surrogate or clinically relevant endpoint

Induction and inhibition of metabolic enzymes concentrations of the drugs. Certain herbal products have been The CYP superfamily is generally involved in oxidative, peroxida- shown to be capable of inducing CYP. Concomitant administra- tive, and reductive biotransformation of xenobiotics and endoge- tion of enzyme-inducing herbal products and prescription drugs nous compounds (Nebert and Russell, 2002; Hiratsuka, 2011). It can therefore result in sub-therapeutic plasma levels of the latter is conventionally divided into families and subfamilies based on with therapeutic failure as a possible clinical consequence. nucleotide sequence homology (Fasinu et al., 2012).Thereisa Apart from enzyme induction, herbal products can also inhibit high degree of substrate specificity among the various families. enzyme activities. The inhibition of CYP and other metabolic CYP belonging to the families 1, 2, and 3 are principally involved enzymes is usually competitive with instantaneous and inhibitor in xenobiotic metabolism while others play a major role in the concentration-dependent effects (Zhang and Wong, 2005). Most formation and elimination of endogenous compounds such as inhibitors are also substrates of CYP (Zhou, 2008). This phenom- hormones, bile acids, and fatty acids (Norlin and Wikvall, 2007; enon alters pharmacokinetic profiles of xenobiotics significantly. Amacher, 2010). The most important CYP subfamilies respon- As a result of the suppression of the anticipated pre-systemic sible for drug metabolism in humans are 1A2, 2A6, 2C9, 2C19, intestinal and hepatic metabolism, unusually high plasma levels 2D6, 2E1, 3A4, and 3A5 (Ono et al., 1996; Wang and Chou, of xenobiotics are observed. Toxic manifestation could be the 2010). ultimate effect of this observation. An equally clinically impor- CYP1A1 and 1A2 are the two major members of the human tant consequence of enzyme inhibition is drug accumulation due CYP1A subfamily. CYP 1A1 is mainly expressed in extra-hepatic to subdued hepatic clearance. These effects will be of particu- tissues such as the kidney, the intestines, and the lungs while lar concerns in drugs with narrow therapeutic window or steep CYP1A2 constitutes about 15% of total hepatic CYP (Martignoni dose–response profiles. et al., 2006). CYP2B6 is involved in drug metabolism while most St John’s wort is one of the most widely used herbal antide- other members of the CYP2B subfamily play less significant meta- pressants (Lawvere and Mahoney, 2005; Høyland, 2011). It is a bolic roles (Pavek and Dvorak, 2008). The subfamily 2C is the potent inducer of CYP3A4 and depending on the dose, dura- second most abundant CYP after 3A representing over 20% of the tion and route of administration, it may induce or inhibit other total CYP present in the human liver. It comprises three active CYP isozymes and P-gp (Roby et al., 2000; Markowitz et al., members: 2C8, 2C9, and 2C19 all of which are also involved 2003b; Tannergren et al., 2004; Madabushi et al., 2006). Stud- in the metabolism of some endogenous compounds including ies from case reports indicate that, due to its inducing effects retinol and retinoic acid (Lewis, 2004). Few clinically relevant on CYP3A4, it significantly reduces the plasma levels of CYP3A4 drugs including paracetamol, chlorzoxazone, and enflurane are substrates including cyclosporine, simvastatin, indinavir, warfarin, metabolized by CYP2E1, the most active of the 2E subfamily amitriptyline, tacrolimus, oxycodone, and nevirapine (Henderson (Leclercq et al., 2000). CYP3A subfamily constitutes over 40% et al., 2002; Johne et al., 2002; Nieminen et al., 2010; Vlachojannis of the total CYP in the human body (although the levels may et al., 2011). It has also been reported that the alteration in the vary 40-fold among individuals) with CYP3A4 being the most blood serum concentration of cyclosporine due to SJW has led to abundant of all isoforms highly expressed in the liver and the organ rejection in patients (Ernst, 2002; Murakami et al., 2006). intestines and participates in the metabolism of about half of Reports of breakthrough bleeding and unplanned pregnancies due drugs in use today (Ferguson and Tyndale, 2011; Singh et al., to interaction between SJW and oral contraceptives have also been 2011). The specificity and selectivity of substrates and inhibitors documented (Hu et al., 2005). The group of drugs with the highest for these enzymes are particularly useful in pharmacokinetic and potential for clinically significant pharmacokinetic drug interac- toxicological studies. tion with SJW is the antidepressants as SJW itself is consumed by Induction is the increase in intestinal and hepatic enzyme patients with depression. Its concomitant use with SSRI like ser- activity as a result of increased mRNA transcription leading to traline and paroxetine has been reported to result in symptoms protein levels higher than normal physiologic values. When this of central serotonergic syndrome (Barbenel et al., 2000; Dannawi, happens, there is a corresponding increase in the rate of drug 2002; Spinella and Eaton, 2002; Birmes et al., 2003; Bonetto et al., metabolism affecting both the oral bioavailability and the sys- 2007). It has also been said to increase the incidence of hypo- temic disposition. In the formulation and dosage design of oral glycemia in patients on tolbutamide without apparent alteration medications, allowance is often made for pre-systemic metabo- in the pharmacokinetic profile of tolbutamide (Mannel, 2004). lism in order to achieve predictable systemic bioavailability. A It also inhibits the production of SN-38, an active metabolite of disruption in this balance can result in significant changes in blood irinotecan, in cancer patients.

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Amitriptyline is a substrate to both CYP3A4 and intestinal P- and tryptophan, an amino acid have been documented as potent gp. The risk of therapeutic failure is thus high due to induction of CYP inhibitors (Rannug et al., 2006). Some herbal medications CYP3A4-dependent metabolism activities resulting in poor oral and their phytochemical constituents capable of interacting with bioavailability. In a study by Johne et al. (2002), a 21% decrease in CYP are presented in Table 3. A more detailed involvement of CYP the area under the plasma concentration–time curve of amitripty- in HDI is detailed in some recently published reviews (Delgoda line was observed in 12 depressed patients who were concomitantly and Westlake, 2004; Pal and Mitra, 2006; Cordia and Steenkamp, administered with extracts of SJW and amitriptyline for 2 weeks. 2011; Liu et al., 2011). Other CYP and P-gp substrates whose pharmacokinetic pro- Phase II metabolic enzymes including uridine diphosphoglu- file have been reportedly altered by SJW include anticoagulants curonosyl transferase (UGT), N -acetyl transferase (NAT), glu- like phenprocoumon and warfarin; antihistamines like fexofena- tathione S-transferase (GST), and sulfotransferase (ST) catalyze dine; antiretroviral drugs including protease inhibitors and reverse the attachment of polar and ionizable groups to phase I metabo- transcriptase inhibitors; hypoglycemic agents such as tolbutamide; lites aiding their elimination. While cytochrome P450-mediated immunosuppressants like cyclosporine, tacrolimus, and mycophe- HDI have been extensively investigated in various studies, the nolic acid; anticonvulsants such as carbamazepine; anti-cancer like effects of herbal extracts on phase II enzymes have not been ade- irinotecan; bronchodilators like theophylline; antitussive like dex- quately studied. However, there is sufficient evidence in literature tromethorphan; cardiovascular drugs like statins, digoxin, and to suggest the potentials of phase II enzymes to induce clinically dihydropyridine calcium channel blockers; oral contraceptives; significant HDI. opiates like methadone and loperamide; and benzodiazepines In a study carried out in rat models by Sheweita et al. (2002), including alprazolam and midazolam (Greeson et al., 2001; Di extracts of hypoglycemic herbs, Cymbopogon proximus, Zygophyl- et al., 2008; Hojo et al., 2011). Following a single dose adminis- lum coccineum, and Lupinus albus reduced the activity of GST and tration of 300 mg standardized extracts of SJW containing 5% GSH. Curcumin, from Curcuma longa, an herbal antioxidant with hyperforin in humans, a maximum plasma concentration of anti-inflammatory and antitumor properties increased the activ- 0.17–0.5 μM hyperforin yielding a [I]/K i > 0.22, in vivo extrap- ity of GST and quinone reductase in the ddY mice liver (Iqbal olation suggests a high possibility of in vivo pharmacokinetic et al., 2003). Valerian, an herbal sleeping aid has also demon- drug interaction (Agrosi et al., 2000). Bray et al. (2002) con- strated the potential of inducing HDI through the inhibition of firmed through animal studies that SJW modulates various CYP UGT. Up to 87% of inhibition of UGT activity by valerian extract enzymes. Dresser et al. (2007) demonstrated that SJW is capable was reported in an in vitro study utilizing estradiol and morphine of inducing CYP3A4 in healthy subjects through the observation as probe substrate (Alkharfy and Frye, 2007). Kampo, a tradi- of increased urinary clearance of midazolam. Thus animal and tional Japanese medicine made of a mixture of several medicinal human studies further confirm SJW as containing both inhibitory herbs has shown inhibitory effects on some phase II enzymes. In and inducing constituents on various CYP isozymes. These effects an in vitro study by Nakagawa et al. (2009), nine out of 51com- may depend on dosage and duration of administration, and may ponents of kampo medicine elicited more than 50% inhibition also be species- and tissue-specific. While the individual phyto- of UGT2B7-mediated morphine 3-glucuronidation. In the same chemical constituents of SJW have elicited varying effects on the study, extracts of kanzo (Glycyrrhizae radix), daio (Rhei rhizoma), metabolic activity of the CYP isozymes, whole extracts and major and keihi (Cinnamomi cortex) elicited more than 80% inhibition constituents especially hyperforin have been reported to inhibit of morphine AZT glucuronidation. This result agrees with Katoh the metabolic activities of CYP1A2, 2C9, 2C19, 2D6, and 3A4 via et al. (2009) who carried out similar studies on rhei, keihi, and in vitro studies and in vivo studies (Lee et al., 2006; Madabushi ogon (Scutellariae radix). et al., 2006; Hokkanen et al., 2011). Apart from the well-known effects on Ginkgo biloba on CYP Ginkgo biloba have been reported to induce CYP 2C19- enzymes as illustrated earlier, its extracts have demonstrated dependent omeprazole metabolism in healthy human subjects potent inhibition of mycophenolic acid glucuronidation inves- (Yin et al., 2004). Piscitelli et al. (2002) in a garlic–saquinavir inter- tigated in human liver and intestinal microsomes (Mohamed and action study reported 51% decrease in saquinavir oral bioavail- Frye, 2010). ability caused by the presence of garlic and attributable to garlic- In a study to investigate the influence of 18 herbal remedies on induced CYP3A4 induction. Its effects on the warfarin pharma- the activity of human recombinant sulfotransferase 1A3 employ- cokinetic has also been reported in animal models (Taki et al., ing dopamine and ritodrine as substrates, extracts of grape seed, 2012). milk thistle, gymnema, SJW, ginkgo leaf, banaba, rafuma, and Although grapefruit juice is not consumed for medicinal pur- peanut seed coat showed potent inhibition with IC50 values lower poses, the discovery of the inhibitory activity of its flavonoid than putative gastrointestinal concentration (Nagai et al., 2009). contents on CYP has led to further researches in medicinal herbs Similarly, Mohamed and Frye (2011b) reported the inhibition of which have revealed HDI potentials in flavonoid-containing herbal UGT1A4 by green tea derived epigallocatechin gallate; UGT 1A6 remedies (Choi and Burm, 2006; Palombo, 2006; Paine et al., 2008; and UGT1A9 by milk thistle; UGT 1A6 by saw palmetto; and Quintieri et al., 2008; Alvarez et al., 2010). A related CYP inhibitor UGT 1A9 by cranberry. A recent publication presents evidence of is rotenone. By interfering with the electron transfer of the heme potential HDI mediated by UGT (Mohamed and Frye, 2011a). iron, rotenone, a naturally occurring phytochemical found in sev- Certain phytochemicals including coumarin, limettin, eral plants such as the jicama vine plant is known to inhibit CYP auraptene, angelicin, bergamottin, imperatorin, and activity (Sanderson et al., 2004). Resveratrol, a natural polymer, isopimpinellin have also been reported to be capable of inducing

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 5 Fasinu et al. Herb–drug interactions , Cox Tang , , Teschke Al-Deeb , Bilgi et al. , , Kim et al. Tang et al. Hafner et al. , , , Methlie et al. , Berginc and Kristl Sevior et al. (2010) , , Roberts and Flanagan Lau et al. (2011) Sarris et al. (2011) , Malati et al. (2011) Hamann et al. (2011) , , , , Li et al. (2009) Nishikawa et al. (2004) Gurley et al. (2005b) (2010) (2010b) (2011) Kent et al. (2002) Hu et al. (2005) (2009) (2010) Scott and Elmer (2002) et al. (2006) Gurley et al. (2005a) et al. (2010) (2011) Mu et al. (2006) De Berardinis etSavvidou et al. al. (2007) (2000) (2009) Markowitz et al. (2003a) et al. (2006) (2012) 4 4 4 4 4 2 3 4 Candidates for interactions LE Reference 3A4 substrates CYP substrates 4 CYP2C19, 2D6, and 3A4 substrates substrates Orally administered CYP substrates Imatinib, CYP2E1, and 2D6 substrates and 3A4 substrates CYP3A4 inducers like Phenobarbital, rifampicin and 3A4 substrates interactions Inhibition of CYP enzymes and P-gp Warfarin, CYP1A2, 2C9, and 3A4 activity Decreased CYP2C19, 2D6, and 3A4 activity Inhibition and induction of CYP and P-gp 2C19, 2D6, and 3A4 activity Production of toxic CYP3A4-induced metabolites flavonoids Kavalactones Decreased CYP1A2, 2D6, 2E1, and Flavonoids, coumarins Inhibition of CYP1A2, 3A4, and P-gp CYP substrates 3 Inhalant Inhibition of CYP2B6, 2C9 and 3A4 CYP2B6, 2C9 and 3A4 Proanthocyanidin, resveratrol Hyperforin, hypericin, flavonoids Glycyrrhizin CYP2C9 and 3A4 inductionGinsenosides Warfarin, Lidocaine, CYP2C9, Inhibition and induction of CYP2C9, Saponins, flavonoids, diterpenoids Anthocyanins, Allicin, phytoncide CYP 3A4 and P-gp induction Saquinavir, warfarin, CYP2D6, Piper methysticum Scientific name Major constituents Mechanism of drug Glycyrrhiza glabra Hypericum perforatum Glycyrrhiza uralensis Panax ginseng Angelica sinensis Allium sativum Vaccinium macrocarpon Vitis vinifera Teucrium chamaedrys Kava kava (root) Medicinal Plant and parts used Cranberry (fruit extract) LE, level of evidence. Dong quai (root) Liquorice (root) Grape seed (seed oil) St John’s wort (aerial parts) Gan cao (root) Ginseng (root) Garlic (bulb) Germander (leaves) Table 3 | Some herbal products known to interact with CYP and efflux proteins.

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hepatic GST activities (Kleiner et al., 2008). While the clinical Borrel et al. (1994) reported that mobile ionophores such as significance of these findings are yet to be determined, it is note- valinomycin, nonactin, nigericin, monensin, calcimycin, and lasa- worthy that phase II metabolic enzymes may play significant roles locid inhibit the efflux of anthracycline by P-gp whereas channel- in HDIs. forming ionophores such as gramicidin do not (Larsen et al., 2000). A number of herbal products which interact with CYP also Inhibition and induction of transport and efflux proteins have similar effects on transport proteins (Table 3). The trans- The ATP-binding cassette (ABC) family of drug transporters plays port proteins are actively involved in the pharmacokinetics of significant roles in the absorption, distribution, and elimination anti-cancer drugs and account for one of the well-known mecha- of drugs. P-gp, the most studied member of this family is a 170- nisms of multiple resistance of cancerous cells to chemotherapeu- kDa plasma glycoprotein encoded by the human MDRI gene. It tic agents (Bebawy and Sze, 2008; Bosch, 2008; He et al., 2011). is constitutively expressed in a number of body tissues and con- The influence of some herbs on transport proteins is presented in centrated on the apical epithelial surfaces of the bile canaliculi of Table 4. Clinically relevant interactions between herbal medicine the liver, the proximal tubules of the kidneys, the pancreatic duc- and chemotherapeutic agents are detailed in a recent review by Yap tal cells, the columnar mucosal cells of the small intestine, colon, et al. (2010). and the adrenal glands (Marzolini et al., 2004; Degorter et al., 2012). It is actively involved in drug absorption and elimination Alteration of gastrointestinal functions from the intestines the liver, kidneys, and the brain. Specifically Besides their influence on the intestinal metabolic enzymes and these proteins are involved in the processes of hepatobiliary, direct efflux proteins,herbal medications can alter the absorption of con- intestinal, and urinary excretion of drugs and their metabolites comitantly administered medicines through a number of mecha- (Szakács et al., 2008). Thus, the modulation of P-gp, or competi- nisms. Changes in the gastrointestinal pH and other biochemical tive affinity as substrates for its binding sites by co-administered factors can alter dissolution properties and the absorption of herbs presents a potential for alteration in the pharmacokinetic pH-dependent drugs such as ketoconazole and itraconazole. Com- profile of the drug. plexation and chelation, leading to the formation of insoluble Pharmacokinetic interaction occurs when herbal drugs inhibit complexes and competition at the sites of absorption especially or decrease the normal activity level of drug transporters through with site-specific formulations can greatly affect the absorption of a competitive or non-competitive mechanism. Interactions can medicines. Anthranoid-containing plants – cassia (Cassia senna), also occur through the induction of transport proteins via the Cascara (Rhamnus purshiana), rhubarb (Rheum officinale), and increase of the mRNA of the relevant protein. Studies have iden- soluble fibers including guar gum and psyllium can decrease drug tified a number of clinically important P-gp inhibitors including absorption by decreasing GI transit time. They are known to phytochemicals – flavonoids, furanocoumarins, reserpine, quini- increase GIT motility. On concomitant use with prescribed med- dine, yohimbine, vincristine, vinblastine among others (Krishna ication, significant alteration in the absorption of the latter has and Mayer, 2001; Zhou et al., 2004; Patanasethanont et al., 2007; been reported due to decreased GI transit time (Fugh-Berman, Iwanaga et al., 2010; Eichhorn and Efferth, 2011; Yu et al., 2011). 2000).

Table 4 | Influence of herbal products on transport proteins.

Drug transporter Anti-cancer substrates Interacting herbal products LE Reference

P-glycoprotein Actinomycin D, daunorubicin, docetaxel, Rosmarinus officinalis 2 Oluwatuyi et al. (2004), (ABCB-1, MDR-1) doxorubicin, etoposide, irinotecan, mitoxantrone, Nabekura et al. (2010) paclitaxel, teniposide, topotecan, vinblastine, vincristine, tamoxifen, mitomycin C, tipifarnib, epirubicin, bisantrene MRP-1 (ABCC-1) Etoposide, teniposide, vincristine, vinblastine, Curcuma longa 2 Shukla et al. (2009) doxorubicin, daunorubicin, epirubicin, idarubicin, topotecan, irinotecan, mitoxantrone, chlorambucil, methotrexate, melphalan MRP-2 (ABCC-2) SN-38G (metabolite of irinotecan), methotrexate, Inchin-ko-to 2 Okada et al. (2007) sulfinpyrazone, vinblastine BCRP (ABCG-2, 9-Aminocamptothecin, daunorubicin, epirubicin, Flavonoid-containing herbs such as 2 Merino et al. (2010), MXR) etoposide, lurtotecan, mitoxantrone, SN-38, Glycine max (soybean), Gymnema Tamaki et al. (2010) topotecan sylvestre, and Cimicifuga racemosa (black cohosh)

LE, level of evidence. ABC, ATP-binding cassette; BCRP,breast cancer resistance protein; MDR, multidrug resistance gene; MRP,multidrug resistance-associated protein; MXR, mitoxantrone resistance-associated protein.

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Table 5 | Some herbal remedies capable of interacting with other drugs via alteration in renal functions.

Medicinal plants Brief description Mechanism LE Reference

Aristolochia fangchi Chinese slimming herbal Aristolochic acid content forms DNA 4 Lai et al. (2010) remedy adducts in renal tissues leading to extensive loss of cortical tubules Djenkol bean (Pithecellobium lobatum) Pungent smelling edible fruit, Contains nephrotoxic djenkolic acid 3 Luyckx and Naicker used for medicinal purposes (2008), Markell (2010) in Africa Impila (Callilepis laureola) Popular South African Causes damage to the proximal convoluted 3 Steenkamp and medicinal herb tubules and the loop of henle, shown to be Stewart (2005) hepatotoxic Wild mushrooms Widely consumed in Africa Some species especially Cortinarius 3 Wolf-Hall (2010) contains nephrotoxic orellanine Licorice root (Glycyrrhiza glabra) Leguminous herb native to Contains glycyrrhizic acid whose 4 Isbrucker and Bur- Europe and Asia, root and metabolite, glycyrrhetinic acid inhibits renal dock (2006), Kataya extracts are used in chronic 11-hydroxysteroid dehydrogenase leading to et al. (2011) hepatitis and other ailments a pseudoaldosterone-like effect – accumulation of cortisol in the kidney, stimulation of the aldosterone receptors in cells of the cortical leading to increased BP,sodium retention, and hypokalemia. This may potentiate the action of drugs such as digoxin Noni fruit (Morinda citrifolia), alfalfa These plants and their Hyperkalemic, hepatotoxic 3 Saxena and Panbo- (Medicago sativa), Dandelion (Taraxacum extracts are used variously in tra (2003), Stadlbauer officinale), horsetail (Equisetum arvense), traditional medicine, and have et al. (2005), Jha stinging nettle (Urtica dioica) been shown to contain very (2010) high potassium levels Rhubarb (Rheum officinale) Used as laxative High oxalic acid content may precipitate 1 Bihl and Meyers renal stone formation and other renal (2001) disorders Star fruit (Averrhoa carambola) A tree popular in Southeast Oxalate nephropathy Chen et al. (2001), Asia and South America Wu et al. (2011) employed traditionally as antioxidant and antimicrobial Uva ursi (Arctostaphylos uva ursi), Various plants used as Plants have diuretic property1 and may 1 Dearing et al. (2001), goldenrod (Solidago virgaurea), dandelion diuretics increase the renal elimination of other drugs Wojcikowski et al. (Taraxacum officinale), juniper berry (2009) (Juniperus communis), horsetail (Equisetum arvense), lovage root (Levisticum officinale), parsley (Petroselinum crispum), asparagus root (Asparagus officinalis), stinging nettle leaf (Urtica dioica), alfalfa (Medicago sativa)

LE, level of evidence. 1Some of these herbs exert their diuretic effects via extra-renal mechanisms with no direct effects on the kidneys (see Dearing et al., 2001).

Izzo et al. (1997) demonstrated that anthranoids could be quinone reductase and glutathione transferase in the gastroin- harmful to the gut epithelium by inhibiting Na+/K+ ATPase and testinal tract of the rat. In view of their roles in metabolism, both increasing the activity of nitric oxide synthase. This significantly enzymes are considered chemoprotective especially from chemical increased intestinal transit due to the alteration in the intestinal carcinogens. In addition to CYP and P-gp mediated mechanisms, water and salt absorption and the subsequent fluid accumulation. the well-known ginseng-induced pharmacokinetic HDI may also InastudyconductedbyMunday and Munday (1999), a garlic- be due to its gastrointestinal effects especially its inhibitory effects derived compound was shown to increase the tissue activities of on gastric secretion (Suzuki et al.,1991). The potential of rhein and

Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 | Article 69 | 8 Fasinu et al. Herb–drug interactions Abii and , (Continued) Balderas et al. (2008) Onuoha (2011) Mohammed et al. (2008) Fabricant and Farnsworth (2001) Lange (2000) Boucher and(2002) Mannan De Almeida et al. (2000) Fugh-Berman (2000) He and Liu (2005) Arteaga et al. (2005) Waako et al. (2005) Wood et al. (2003) Taylor (2000) 4 LE Reference 3 Muscle relaxants 1 Cholinergic agents, CNS drugs Diuretics, laxatives 2 Steroids 3 for potential interactions Hypoglycemic agents, immunosuppressants Warfarin 4 which at high doses produces a depolarizing block of nerve transmission agonist Diuretic, choleretic, cholagogue dependent interaction Estrogenic activity, hepatotoxicity Hypoglycemic, immunostimulants Anticholinergic Cholinomimetics 1 hepatic disorders SedativeCardiotonic Sedative synergy Positive inotrope Sedatives, hypnotics Cardiovascular drugs 2 1 circulatory shock in China RTI, chicken pox, TB, STI, pain, TB, weight loss Indications Mechanism of action Drug candidates Energy replenishing agent, diabetes, liver, and kidney diseases digoxin, digitoxin, gitalin, lanatosides Essential oils: monoterpenes Lignans, flavonoids, volatile oils, amino acids ingredients Glycoproteins, polysaccharides, vitamin C Alkaloids, tannins Malaria Antagonism Artemisinin, chloroquine 1 Acetyldigoxin, digitalin, Anabasine Skeletal muscle relaxant Nicotinic receptor agonist Anisodine, AnisodamineAdoniside Used in treating acute Cardiotonic Cardiostimulant Cardiovascular drugs 1 Anthracene glycosides laxative Increasing GIT motility Orally administered drugs 1 Anthocyanins, flavonoids Antioxidant VKORC1* genotype (Boldo) Boldine Indigestion, constipation, Grecian (pheasant’s (Betel nut) Arecoline Relaxing drug Direct acting cholinergic Digitalis lanata ( foxglove, wooly foxglove) eye, red chamomile) Peumus boldus Rhamnus purshiana (Cascara) Larrea tridentata (Chaparral) Medicinal plant Major active Lyceum barbarum (Chinese wolfberry) Aspilia africana Anabasis sphylla Anisodus tanguticus Adonis vernalis Areca catechu Vaccinium macrocarpon Ternstroemia pringlei Table 6 | Some examples of pharmacodynamic interactions between herbal products and conventional drugs.

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 9 Fasinu et al. Herb–drug interactions , , , Cir- Gilca , Young Asdaq , , , Wu and , Shi et al. (2005) Barnes et al. (2005) Galíndez et al. (2002) Moorthy etBaquer et al. al. (2011) (2010) Ni et al. (2010) Crijns et al.et (2002) al. (2010) and Inamdar (2011) Lala et al.et al. (2004) (2006) Goh and Lohcosta et (2001) al. (2006) Rogers et al. (2000) Ferrara et al. (2001) Asdaq et al. (2009) Wilasrusmee et al. (2002) Yeung (2010) Tripathi and Chandra (2010) Yagmur et al. (2005) LE Reference 3 3 3 3 2 3 3 1 for potential interactions anticoagulants Immunosuppressants, hypoglycemic agents Oral hypoglycemic agents 2 metabolism Diclofenac, anticoagulants 3 Contraceptives, vasodilators, anticoagulants, antiplatelets antiplatelets anticoagulants Propranolol, hypoglycemic agents, anticoagulants Sedatives, hypnotics, and anxiolytics Anticoagulants, Antiplatelets, Anti-arrhythmias 3 hypoglycemic hypoglycemic, cholagogue Immunostimulants Immunosuppressants 3 antiulcer Estrogenic, vasorelaxant, anti-inflammatory function prostaglandin release, thus altering platelet function antidiabetic, antiplatelet, antilipidemic anti-arrhythmic, positive inotropic stimulants, antilipidemic Immunomodulatory, Antilipidemic, Alteration in platelet Antihypertensive, Anti-inflammatory, Antioxidants, CNS IndicationsCardiovascular diseases Mechanism Vasorelaxants, of antiplatelets action Warfarin, vasodilators, Drug candidates Diabetes, hypercholesterolemia Upper respiratory tract infections Gynecological and circulation disorders Cardioprotection, dementia, antioxidant prevention of arteriosclerosis arthritic pain prevention of cancer Loss of energy and memory, stress, male sexual dysfunction ingredients compounds saponins polysaccharides Phytoestrogens, flavonoids, coumarins ginkgolic acid Parthenolide, tanetin Headache, fever, arthritis Inhibition of serotonin and Harpagophy cumbens Musculoskeletal and Polyphenols, caffeine Cardiovascular diseases, (ginsenosides) Alkaloids, flavonoids, Alkaloids Gallstones, dyspepsia Hepatotoxicity Liver-dependent (Ginger) Zingerone, gingerols Nausea, dyspepsia Antiemetic, antiplatelet, (Green (Dong (Danshen) Tanshinones, phenolic (Garlic) Allins Hypercholesterolemia, (Ginseng) Triterpene saponins (Ginko) Flavonoids, ginkgolides, (Devils claw) species Alkamides, phenols, Medicinal plantSalvia miltiorriza Major active (Fenugreek) quai) (Feverfew) Echinacea Chelidonium majus (Greater celandine) Camellia sinensis tea) Zingiber officinale Ginko biloba Panax ginseng Harpagophytum procumbes Angelica sinensis Allium sativum Trigonella foenum-graecum Tanacetum parthenium Table 6 | Continued

Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 | Article 69 | 10 Fasinu et al. Herb–drug interactions (Continued) Szolomicki et al. (2000) Huxtable(2000) and Cooper Sztajnkrycer et al. (2008) Ono et al. (2000) Shekelle et al. (2003) Feltenstein et al. (2003) Emma (2008) Stewart et al. (2002) Mukhtar et al. (2006) Albert et al. (2002) Armanini et al. (2002) Al-Habori (2005) 2 3 1 2 3 Contraceptives 4 Immunosuppressants 4 antihypertensives Diuretics, antihypertensives anti-arrhythmic, vasodilators Sedative/hypnotic/ anxiolytics metabolism Hypoglycemic agents 2 Anticoagulants, Antihypertensives, Hepatoprotective, anti-osteoporosis Immunomodulatory, anti-inflammatory, antitumor functions effects (mineralocorticoid actions) expectorant, anti-inflammatory sympathomimetic muscle relaxants Hepatotoxicity Liver-dependent Hypoglycemic, antilipidemic Antiulcer, aldosterone-like prevention of heart diseases and cancer memory, stress, male sexual dysfunction inflammation cough, worm infestations Diabetes, obesity, hypercholesterolemia Eleutherosides Loss of energy and Pyrrolizidine alkaloids Herbal teas and enemas Hepatotoxicity Liver-metabolized drugs 2 Pulgenone Abortifacient, herbal tonic Hepatotoxicity Most drugs 2 Ephedrine Weight loss Hepatotoxicity CNS drugs 3 Glycyrrhizinic acid Gastric ulcer, catarrhs, Galactomannan, lipids, saponin Tetrahydropalmatine Sedative, analgesic Hepatotoxicity CNS drugs 3 (Jin a (Kava) Kavapyrones Anxiety, insomnia Anxiolytic, anesthetic, (Impila) Atractyloside GIT disorders, fertility, (Papaya) Papain GIT disorders Alteration in platelet species, (Soya) Phytoestrogens Menopausal symptoms, (Khat) Cathinone Loss of energy CNS stimulant, indirect (Siberian species species, Glycine max Eleutherococcus senticosus ginseng) Heliotropium senecio symphytum crotalari (Pyrrolizidines) Mentha pulegium (Pennyroyal) Carica papaya Ephedra (Ma-huang) Glycyrrhiza glabra (Liquorice) Catha edulis Piper methysticum Lycopodium serratum Bu huan) Callilepsis laureola Cyamopsis tetragonolobus (Guar gum)

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 11 Fasinu et al. Herb–drug interactions Scott et al. (2005) Ulbricht et al. (2008) Bafna and Mishra (2010) Knight and Walter (2002) Emilio et al. (1998) Maridass and(2008) De Britto Gilani et al. (2008) Ziment and Tashkin (2000) Schoner (2000) Hsieh et al. (2008) Gaillard and Pepin (2001) Marx et al. (2005) Ashihara and Crozier (2001) Agra et al. (2007) Ayuba and Ofojekwu (2005) Ajayi et al. (2003) Yao and Jiang (2002) LE Reference for potential interactions Anticoagulants 3 functions Anticholinergic Cholinergic drugs 1 Antihypertensive Cardiovascular drugs 3 Indications Mechanism of action Drug candidates Stomach disorder, jaundice Alteration in platelet disorders tranquilizer ingredients Saponins, flavonoids, sesquiterpenes, tannins Convallatoxin Cardiotonic Cardiostimulant Cardiovascular drugs 3 CaffeineCissampeline CNSDeserpidine, stimulant reserpine Skeletal muscle relaxant Antihypertensive, Muscle relaxants CNS stimulant Muscle relaxants CNS drugs 2 1 Glasiovine Antidepressant Antidepressant CNS drugs 3 Hyoscyamine GIT disorders Anticholinergic Cholinergic drugs 3 Atropine Motion sickness, GIT Tetrandrine Antihypertensive Antihypertensive effects Cardiovascular drugs 2 (Lily of (Deadly Medicinal plant Major active *VKORC1, vitamin K epoxide reductase complex subunit 1. (Tamarind) nightshade) the valley) Camellia sinensis, species Cissampelos pareira (Velvet) Convallaria majalis Rauwolfia canescens; Rauwolfia serpentina Octea glaziovii Black henbane, stinking nightshade, henpin KhetinOuabain treeCalabar beanJaborandi, Indian hemp Pilocarpine Ouabain Kheltin Physostigmine Purgative Cardiotonic Asthma Parasympathomimetic Cardiostimulant Cholinergic drugs Bronchodilator Cholinesterase inhibitor Cardiovascular drugs Cholinergic drugs 3 Anti-asthma drugs 1 3 1 squillJimsonweed Scopolamine Scillarin A Sedative Cardiotonic Sedative Sedative Cardiovascular drugs Cardiovascular drugs 2 1 Atropa belladonna White false hellebore Protoveratrines A, B Antihypertensives Antihypertensive Cardiovascular drugs 3 Tamarindus indica Theobroma cacao, Thea Yohimbe Yohimbine Aphrodisiac Vasodilatory Cardiovascular drugs 2 Table 6 | Continued

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danthron to increase the absorption of furosemide, a poorly water- while some others act as direct tubular irritants (Crosby et al.,2001; soluble drug, has been demonstrated through in vitro studies Al-Ali et al., 2003). Some herbs capable of interacting with renal (Laitinen et al., 2007). In a study carried out on mice, a Chi- functions and drug elimination are presented in Table 5. nese herbal plant, Polygonum paleaceum, showed the potential to depress the motility of the gastrointestinal tract, inhibit defeca- Pharmacodynamic synergy, addition, and antagonism tion reflex and delay gastric emptying (Zhang, 2002). A similar Herb–drug interaction can occur through the synergistic or addi- study demonstrated the inhibitory effects of two Chinese tradi- tive actions of herbal products with conventional medications as tional herbal prescriptions, Fructus aurantii immaturus and Radix a result of affinities for common receptor sites (Ma et al., 2009). paeoniae alba on gastrointestinal movement (Fang et al., 2009). This can precipitate pharmacodynamic toxicity or antagonistic The absorption of drugs such as phenoxymethylpenicillin,met- effects (Table 6). Like most other herbs, SJW contains complex formin, glibenclamide, and lovastatin may be reduced by high- mixture of phytochemicals including phenylpropanes, naphtho- fiber herbal products through the sequestration of bile acids danthrones, acylphloroglucinols, flavonoids, flavanol glycosides, (Colalto, 2010). Mochiki et al. (2010) reported the ability of and biflavones. Hyperforin is known to inhibit the reuptake of Kampo, a traditional Japanese medicine, to stimulate elevated neurotransmitters (dopamine, serotonin, noradrenalin) and is intestinal blood flow, and to induce increased secretion of gas- believed to be the bioactive responsible for the antidepressant trointestinal hormones including motilin, vasoactive intestinal activity of SJW. peptide, and calcitonin gene-related peptide. Similarly, another traditional Japanese medicine has been shown to increase the CONCLUSION intestinal secretion of ghrelin, a hunger-related hormone, lead- Concomitant use of herbs and conventional drugs may present ing to delayed gastric emptying (Tokita et al., 2007; Kawa- with untoward events. Evidence available in literature indicates hara et al., 2009; Hattori, 2010; Matsumura et al., 2010). Also, various mechanisms through which this can occur. By interacting Qi et al. (2007) demonstrated the capability of Da-Cheng-Qi- with conventional medication, herbal remedies may precipitate Tang, a traditional Chinese herbal formula, to increase plasma manifestations of toxicity or in the other extreme, therapeutic motilin, enhance gastrointestinal motility, improve gastric dys- failure. A good knowledge of the potential of commonly con- rhythmia, and reduce gastroparesis after abdominal surgery. These sumed herbal medicines to interact with prescription medicines, effects have the potential of reducing the intestinal transit time irrespective of the nature of evidence available, will equip health of concurrently administered drug, with the risk of reduced professionals in their practice. Apart from those demonstrated in absorption. significant number of human subjects, not all reported HDIs are clinically significant. As such, more clinically relevant research in Alteration in renal elimination this area is necessary. This review provides information on com- This involves herbal products capable of interacting with renal monly used herbs and their potentials for HDI within the levels of functions,leading to altered renal elimination of drugs. Such inter- evidence currently available. action can result from the inhibition of tubular secretion, tubular reabsorption, or interference with glomerular filtration (Isnard ACKNOWLEDGMENTS et al., 2004). In addition to this group of herbal products are The authors will like to acknowledge the support of HOPE those products consumed as diuretics. The mechanism of herbal Kapstadt-Stiftung (HOPE Cape Town) and the Stellenbosch diuresis is complex and non-uniform. Certain herbs increase the University Rural Medical Education Partnership Initiative glomerular filtration rate but do not stimulate electrolyte secretion (SURMEPI) for providing funds for this study.

REFERENCES A. O. (2003). Endothelin-like from Glycine max (L.) Merr in cli- ABC transporters (P-glycoprotein, Abii, T. A., and Onuoha, E. N. (2011). action of Pausinystalia yohimbe macteric symptomatology: a multi- MRP2, BCRP) by flavonoids and The chemical constituents of the aqueous extract on vascular and centric, open, prospective and non- drug response. J. Pharm. Sci. 99, leaf of Aspilia africana as a sci- renal regional hemodynamics in randomized trial. Phytomedicine 9, 598–617. entific backing to its tradomedical Sprague Dawley rats. Methods 85–92. Amacher, D. E. (2010). The effects potentials. Agric. J. 6, 28–30. Find. Exp. Clin. Pharmacol. 25, Al-Deeb, I. D., Arafat, T. A., and Irshaid, of cytochrome P450 induction by Agra, M. F., De Freitas, P. F., and 817–822. Y. M. (2010). The effect of Licorice xenobiotics on endobiotic metab- Barbosa-Filho, J. M. (2007). Synop- Al-Ali, M., Wahbi, S., Twaij, H., and Al- drink on the systemic exposure of olism in pre-clinical safety stud- sis of the plants known as medi- Badr, A. (2003). Tribulus terrestris: Verapamil in rabbits. Drug Metab. ies. Toxicol. Mech. Methods 20, cinal and poisonous in Northeast preliminary study of its diuretic and Lett. 4, 173–179. 159–166. Brazil. Rev. Bras. Farmacogn. 17, contractile effects and comparison Al-Habori, M. (2005). The potential Armanini, D., Fiore, C., Mattarello, M. 114–140. with Zea mays. J. Ethnopharmacol. adverse effects of habitual use of J., Bielenberg, J., and Palermo, M. Agrosi, M., Mischatti, S., Harrasser, 85, 257–260. Catha edulis (khat). Expert Opin. (2002). History of the endocrine P. C., and Savio, D. (2000). Oral Albert, A., Altabre, C., Baró, F., Buendía, Drug Saf. 4, 1145–1154. effects of Licorice. Exp. Clin. bioavailability of active principles E., Cabero, A., Cancelo, M. J., Alkharfy, K. M., and Frye, R. F. (2007). Endocrinol. Diabetes 110, 257–261. from herbal products in humans: Castelo-Branco, C., Chantre, P., Effect of valerian, valerian/hops Arteaga, I., Andrade-Cetto, A., and Cár- astudyonHypericum perforatum Duran, M., Haya, J., Imbert, P., extracts, and valerenic acid on glu- denas, R. (2005). Larrea triden- extracts using the soft gelatin cap- Julía, D., Lanchares, J. L., Llaneza, curonidation in vitro. Xenobiotica tata (Creosote bush), an abundant sule technology. Phytomedicine 7, P., Manubens, M., Miñano, A., 37, 113–123. plant of Mexican and US-American 455–462. Quereda, F., Ribes, C., and Vázquez, Alvarez, A. I., Real, R., Perez, M., Men- deserts and its metabolite nordihy- Ajayi, A. A., Newaz, M., Hercule, H., F. (2002). Efficacy and safety of a doza, G., Prieto, J. G., and Merino, G. droguaiaretic acid. J. Ethnopharma- Saleh, M., Bode, C. O., and Oyekan, phytoestrogen preparation derived (2010). Modulation of the activity of col. 98, 231–239.

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 13 Fasinu et al. Herb–drug interactions

Asdaq, S. M., and Inamdar, M. N. chemistry, pharmacology and clin- Boullata, J. I., and Nace, A. M. (2000). Seaforth,C. E. (2005).A gap between (2010). Pharmacodynamic inter- ical properties. J. Pharm. Pharmacol. Safety issues with herbal medicine. acceptance and knowledge of herbal action of captopril with garlic 57, 929–954. Pharmacotherapy 20, 257–269. remedies by physicians: the need in isoproterenol-induced myocar- Bebawy, M., and Sze, D. M. (2008). Tar- Bray, B. J., Perry, N. B., Menkes, D. for educational intervention. BMC dial damage in rat. Phytother. Res. 24, geting P-glycoprotein for effective B., and Rosengren, R. J. (2002). St Complement. Altern. Med. 5, 20. 720–725. oral anti-cancer chemotherapeutics. John’s wort extract induces CYP3A doi:10.1186/1472-6882-5-20 Asdaq, S. M., and Inamdar, M. N. Curr. Cancer Drug Targets 8, 47–52. and CYP2E1 in the Swiss Webster Colalto, C. (2010). Herbal interactions (2011). Pharmacodynamic and Bensoussan, A., Myers, S. P., Wu, S. M., mouse. Toxicol. Sci. 66, 27–33. on absorption of drugs: mechanisms pharmacokinetic interactions of O’Connor, K. (2004). Naturopathic Brown, L., Heyneke, O., Brown, D., of action and clinical risk assess- propranolol with garlic (Allium and Western herbal medicine prac- van Wyk, J. P., and Hamman, J. H. ment. Pharmacol. Res. 62, 207–227. sativum) in rats. Evid. Based ticeinAustralia–aworkforcesurvey. (2008). Impact of traditional medi- Coppola, M., and Mondola, R. (2012). Complement. Alternat. Med. 2011, Complement. Ther. Med. 12, 17–27. cinal plant extracts on antiretroviral Potential action of betel alkaloids 824042. Berginc, K., and Kristl, A. (2012). The drug absorption. J. Ethnopharmacol. on positive and negative symptoms Asdaq, S. M., Inamdar, M. N., and Asad, effect of garlic supplements and phy- 119, 588–592. of schizophrenia: a review. Nord. J. M. (2009). Effect of conventional tochemicals on the ADMET prop- Calixto, J. B. (2000). Efficacy, safety, Psychiatry 66, 73–78. antihypertensive drugs on hypolipi- erties of drugs. Expert Opin. Drug quality control, marketing and reg- Cordia, W., and Steenkamp, V. (2011). demic action of garlic in rats. Indian Metab. Toxicol. 8, 295–310. ulatory guidelines for herbal med- Drug interactions in African herbal J. Exp. Biol. 47, 176–181. Bihl, G., and Meyers, A. (2001). Recur- icines (phytotherapeutic agents). remedies. Drug Metabol. Drug Inter- Ashihara, H., and Crozier, A. (2001). rent renal stone disease – advances Braz. J. Med. Biol. Res. 33, 179–189. act. 26, 53–63. Caffeine: a well-known but little in pathogenesis and clinical manage- Capasso, F., Gaginella, T. S., Grandolini, Cox, M. C., Low, J., Lee, J., Walshe, J., mentioned compound in plant sci- ment. Lancet 358, 651–656. G., and Izzo, A. A. (2003). Phytother- Denduluri, N., Berman, A., Perme- ence. Trends Plant Sci. 6, 407–413. Bilgi, N., Bell, K., Ananthakrishnan, A. apy: A Quick Reference to Herbal nter, M. G., Petros, W. P., Price, D. Aungst, B. J. (2000). Intestinal perme- N., and Atallah, E. (2010). Imatinib Medicine. Berlin: Spriger-Verlag. K., Figg, W. D., Sparreboom, A., and ation enhancers. J. Pharm. Sci. 89, and Panax ginseng: a potential inter- Cassidy, A. (2003). Are herbal remedies Swain,S. M. (2006). Influence of gar- 429–442. action resulting in liver toxicity. Ann. and dietary supplements safe and lic (Allium sativum) on the pharma- Ayuba, V. O., and Ofojekwu, P. C. Pharmacother. 44, 926–928. effective for breast cancer patients? cokinetics of docetaxel. Clin. Cancer (2005). “Effects of extracts of dried Birmes, P., Coppin, D., Schmitt, L., and Breast Cancer Res. 5, 300–302. Res. 12, 4636–4640. seeds of toloache, Datura innoxia as Lauque, D. (2003). Serotonin syn- Chan, T. Y. (2001). Interaction between Crijns, A. P., se Smet, P. A., van anaesthesia on the African catfish drome: a brief review. CMAJ 168, warfarin and danshen (Salvia mil- den Heuvel, M., Schot, B. W., and Clarias gariepinus fingerlings,” in 1439–1442. tiorrhiza). Ann. Pharmacother. 35, Haagsma, E. B. (2002). Acute hepati- 19th Annual Conference of the Fish- Bodeker, G. (2007). Traditional health 501–504. tis after use of a herbal preparation eries Society of Nigeria. Available at: systems: policy, biodiversity, and Chao, M. T., Wade, C., and Kronen- with greater celandine (Chelidonium http://aquaticcommons.org/3986/ global interdependence. J. Altern. berg, F. (2008). Disclosure of com- majus). Ned. Tijdschr. Geneeskd. 19, 1/25.pdf [accessed November 03, Complement. Med. 1, 231–243. plementary and alternative medicine 124–128. 2011]. Bonetto,N.,Santelli,L.,Battistin,L.,and to conventional medical providers: Crosby, E. C., Dolan, R. L., Benson, Bafna, A., and Mishra, S. (2010). Cagnin, A. (2007). Serotonin syn- variation by race/ethnicity and type J. E., Luetkemeier, M. J., Barton, Antioxidant and immunomodula- drome and rhabdomyolysis induced of CAM. J. Natl. Med. Assoc. 100, R. G., and Askew, E. W. (2001). tory activity of the alkaloidal frac- by concomitant use of triptans, flu- 1341–1349. Herbal diuretic induced dehydration tion of Cissampelos pareira linn. Sci. oxetine and hypericum. Cephalalgia Chen, C. L., Fang, H. C., Chou, K. and resting metabolic rate. Med. Sci. Pharm. 78, 21–31. 27, 1421–1423. J., Wang, J. S., and Chung, H. M. Sports Exerc. 33, S163. Balderas, J. L., Reza, V., Ugalde, M., Borrel, M. N., Pereira, E., Fiallo, M., (2001). Acute oxalate nephropathy Cullen, J. M. (2005). Mechanistic clas- Guzmán, L., Serrano, M. I., Aguilar, and Garnier-Suillerot, A. (1994). after ingestion of star fruit. Am. J. sification of liver injury. Toxicol. A., and Navarrete, A. (2008). Phar- Mobile ionophores are a novel Kidney Dis. 37, 418–422. Pathol. 33, 6–8. macodynamic interaction of the class of P-glycoprotein inhibitors. Cheng, B., Hung, C. T., and Chiu, W. Dannawi, M. (2002). Possible serotonin sedative effects of Ternstroemia The effects of ionophores on 4- (2002). Herbal medicine and anaes- syndrome after combination of bus- pringlei (Rose) Standl. with six cen- O-tetrahydropyranyl-adriamycin thesia. Hong Kong Med. J. 8,123–130. pirone and St John’s wort. J. Psy- tral nervous system depressant drugs incorporation in K562 drug- Chitturi, S., and Farrell, G. C. (2000). chopharmacol. (Oxford) 16, 401. in mice. J. Ethnopharmacol. 119, resistant cells. Eur. J. Biochem. 223, Herbal hepatotoxicity: an expanding Dasgupta, A., Kidd, L., Poindexter, B. 47–52. 125–133. but poorly defined problem. J. Gas- J., Bick, R. J. (2010). Interference of Baquer, N. Z., Kumar, P., Taha, A., Kale, Borrelli, F., Capasso, R., and Izzo, A. A. troenterol. Hepatol. 15, 1093–1099. hawthorn on serum digoxin mea- R. K., Cowsik, S. M., and McLean, (2007). Garlic (Allium sativum L.): Chitturi, S., and Farrell, G. C. (2008). surements by immunoassays and P. (2011). Metabolic and molec- adverse effects and drug interactions Hepatotoxic slimming aids and pharmacodynamic interaction with ular action of Trigonella foenum- in humans. Mol. Nutr. Food Res. 51, other herbal hepatotoxins. J. Gas- digoxin. Arch. Pathol. Lab. Med. 134, graecum (fenugreek) and trace met- 1386–1397. troenterol. Hepatol. 23, 366–373. 1188–1192. als in experimental diabetic tissues. Borrelli, F., and Izzo,A. A. (2009). Herb- Choi, J. S., and Burm, J. P. (2006). De Almeida, E. R., Melo, A. M., and J. Biosci. 36, 383–396. drug interactions with St John’s wort Enhanced nimodipine bioavailabil- Xavier,H. (2000). Toxicological eval- Barbenel, D. M., Yusufi, B., O’Shea, (Hypericum perforatum): an update ity after oral administration of uation of the hydro-alcohol extract D., and Bench, C. J. (2000). Mania on clinical observations. AAPS J. 11, nimodipine with morin, a flavonoid, of the dry leaves of Peumus boldus in a patient receiving testosterone 710–727. in rabbits. Arch. Pharm. Res. 29, and boldine in rats. Phytother. Res. replacement postorchidectomy tak- Bosch, T. M. (2008). Pharmacoge- 333–338. 14, 99–102. ing St John’s wort and sertraline. J. nomics of drug-metabolizing Circosta, C., Pasquale, R. D., Palumbo, De Berardinis, V., Moulis, C., Mau- Psychopharmacol. 14, 84–86. enzymes and drug transporters in D. R., Samperi, S., and Occhi- rice, M., Beaune, P., Pessayre, D., Barnes, J., Anderson, L. A., Gibbons, S., chemotherapy. Methods Mol. Biol. uto, F. (2006). Estrogenic activity Pompon, D., and Loeper, J. (2000). and Phillipson, J. D. (2005). Echi- 448, 63–76. of standardized extract of Angelica Human microsomal epoxide hydro- nacea species (Echinacea angustifo- Boucher, B. J., and Mannan, N. (2002). sinensis. Phytother. Res. 20, 665–669. lase is the target of germander- lia (DC.) Hell, Echinacea pallida Metabolic effects of the consump- Clement, Y. N., Williams, A. F., Khan, induced autoantibodies on the sur- (Nutt.) Nutt., Echinacea purpurea tion of Areca catechu. Addict. Biol. 7, K., Bernard, T., Bhola, S., Fortuné, face of human hepatocytes. Mol. (L.) Moench: a review of their 103–110. M., Medupe, O., Nagee, K., and Pharmacol. 3, 542–551.

Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 | Article 69 | 14 Fasinu et al. Herb–drug interactions

De Maat, M. M., Hoetelmans, R. report. Eur. J. Gastroenterol. Hepatol. Gaillard, Y., and Pepin, G. (2001). Case Hattori, T. (2010). Rikkunshito and M. W., Mathôt, R. A., van Gorp, 20, 469–471. report: LC–EI-MS determination of ghrelin. Int. J. Pept. 2010,pii: 283549. E. C., Meenhorst, P. L., Mulder, Engelberg, D., McCutcheon, A., and veratridine and cevadine in two fatal He, L., and Liu, P. (2005). Effect J. W., and Beijnen, J. H. (2001). Wiseman, S. (2001). A case of cases of Veratrum album poisoning. of Lycium barbarum polysaccha- Drug interactions between St John’s ginseng-induced mania. J. Clin. Psy- J. Anal. Toxicol. 25, 481–485. rides on oxidative stress of dia- wort and nevirapine. AIDS 15, chopharmacol. 21, 535–537. Galíndez, J. S., Lanza, A. M. D., and betic nephropathy in type 2 dia- 420–421. Ernst, E. (2002). St John’s wort sup- Matellano, L. F. (2002). Biologically betic rats. Chinese J. Hosp. Pharm. 12, Dearing, D. M., Mangione, A. M., and plements endanger the success of active substances from the genus 34–40. Karasov, W. H. (2001). Plant sec- organ transplantation. Arch. Surg. Scrophularia. Pharm. Biol. 40,45–59. He, S. M., Li, R., Kanwar, J. R., ondary compounds as diuretics: an 137, 316–319. Gilani, A. H., Khan, A. U., Raoof, and Zhou, S. F. (2011). Struc- overlooked consequence. Am. Zool. Ernst, E. (2004). Are herbal medicines M., Ghayur, M. N., Siddiqui, B. S., tural and functional properties of 41, 890–901. effective? Int. J. Clin. Pharmacol. Vohra, W., and Begum, S. (2008). human multidrug resistance pro- Déciga-Campos, M., Rivero-Cruz, I., Ther. 42, 157–159. Gastrointestinal, selective airways tein 1 (MRP1/ABCC1). Curr. Med. Arriaga-Alba, M., Castañeda-Corral, Ernst, E. (2005). The efficacy of herbal and urinary bladder relaxant effects Chem. 18, 439–481. G., Angeles-López, G. E., Navar- medicine – an overview. Fundam. of Hyoscyamus niger are mediated Henderson, L., Yue, Q. Y., Bergquist, rete, A., and Mata, R. (2007). Acute Clin. Pharmacol. 19, 405–409. through dual blockade of mus- C., Gerden, B., and Arlett, P. (2002). toxicity and mutagenic activity of Fabricant, D. S., and Farnsworth, N. R. carinic receptors and Ca2+ chan- St John’s wort (Hypericum perfora- Mexican plants used in traditional (2001). The value of plants used in nels. Fundam. Clin. Pharmacol. 22, tum): drug interactions and clinical medicine. J. Ethnopharmacol. 110, traditional medicine for drug dis- 87–99. outcomes. Br. J. Clin. Pharmacol. 54, 334–342. covery. Environ. Health Perspect. 109, Gilca, M., Gaman, L., Panait, E., Stoian, 349–356. Degorter, M. K., Xia, C. Q., Yang, J. J., 69–75. I., and Atanasiu, V. (2010). Che- Hiratsuka, M. (2011). In vitro assess- and Kim, R. B. (2012). Drug trans- Fakeye,T.O.,and Onyemadu,O. (2008). lidonium majus –anintegrative ment of the allelic variants of porters in drug efficacy and toxicity. Evaluation of knowledge base of review: traditional knowledge ver- cytochrome P450. Drug Metab. Annu. Rev. Pharmacol. Toxicol. 52, hospital pharmacists and physi- sus modern findings. Forsch. Kom- Pharmacokinet. [Epub online ahead 249–273. cians on herbal medicines in South- plementmed. 17, 241–248. of print]. DeLeve, L. D., Schulman, H. M., and western Nigeria. Pharm. Pract. 6, Giveon, S. M., Liberman, N., Klang, Hojo,Y.,Echizenya, M., Ohkubo, T., and MacDonald, G. B. (2002). Toxic 88–92. S., and Kahan, E. (2004). Are peo- Shimizu, T. (2011). Drug interaction injury to hepatic sinusoids: sinu- Fang, Y. S., Shan, D. M., Liu, J. W., ple who use ‘natural drugs’ aware of between St John’s wort and zolpidem soidal obstruction syndrome (veno- Xu, W., Li, C. L., Wu, H. Z., and their potentially harmful side effects in healthy subjects. J. Clin. Pharm. occlusive disease). Semin. Liver Dis. Ji, G. (2009). Effect of constituents and reporting to family physician? Ther. 36, 711–715. 22, 27–42. from fructus Aurantii immaturus Patient Educ. Couns. 53, 5–11. Hokkanen, J., Tolonen, A., Mattila, S., Delgoda, R., and Westlake, A. C. G. and radix Paeoniae alba on gastroin- Goh,S.Y.,and Loh,K. C. (2001). Gynae- and Turpeinen, M. (2011). Metab- (2004). Herbal interactions involv- testinal movement. Planta Med. 75, comastia and the herbal tonic “dong olism of hyperforin, the active con- ing cytochrome P450 enzymes: 24–31. quai.”Singapore Med. J. 42, 115–116. stituent of St. John’s wort, in human a mini review. Toxicol. Rev. 23, Farkas, D., Shader, R. I., von Moltke, Greeson, J. M., Sanford, B., and liver microsomes. Eur. J. Pharm. Sci. 239–249. L. L., and Greenblatt, D. J. (2010). Monti, D. A. (2001). St. John’s 42, 273–284. Di,Y. M., Li, C. G., Xue, C. C., and Zhou, “Mechanisms and consequences of wort (Hypericum perforatum): a Homsy, J., King, R., Tenywa, J., Kyeyune, S. F.(2008). Clinical drugs that inter- drug–drug interactions,”in Pharma- review of the current pharmacolog- P.,Opio,A.,Balaba,D. (2004). Defin- act with St. John’s wort and impli- ceutical Sciences Encyclopedia: Drug ical, toxicological, and clinical lit- ing minimum standards of practice cation in drug development. Curr. Discovery, Development, and Manu- erature. Psychopharmacology (Berl.) for incorporating African traditional Pharm. Des. 14, 1723–1742. facturing (John Wiley & Sons, Inc.). 153, 402–414. medicine into HIV/AIDS preven- Dresser, G. K., Schwarz, U. I.,Wilkinson, doi: 10.1002/9780470571224.pse055 Gurley, B. J., Gardner, S. F., Hubbard, tion, care, and support: a regional G. R., and Kim, R. B. (2007). Coordi- Fasinu, P., Bouic, P. J., and Rosenkranz, M. A., Williams, D. K., Gentry, W. B., initiative in eastern and southern nate induction of both cytochrome B. (2012). Liver-based in vitro tech- Cui, Y., and Ang, C. Y. (2005a). Clin- Africa. J. Altern. Complement. Med. P4503A and MDR1 by St John’s wort nologies for drug biotransformation ical assessment of botanical supple- 10, 905–910. in healthy subjects. Clin. Pharmacol. studies–areview.Curr.DrugMetab. mentation on cytochrome P450 phe- Howell, L., Kochhar, K., Saywell, R. Jr., Ther. 73, 41–50. 13, 215–224. notypes in the elderly: St John’s wort, Zollinger, T., Koehler, J., Mandzuk, Durazo, F. A., Lassman, C., Han, S. H., Feltenstein, M. W., Lambdin, L. C., garlic oil, Panax ginseng, and Ginkgo C., Sutton, B., Sevilla-Martir, J., and Saab, S., Lee, N. P., Kawano, M., Ganzera, M., Ranjith, H., Dhar- biloba. Drugs Aging 22, 525–539. Allen, D. (2006). Use of herbal reme- Saggi, B., Gordon, S., Farmer, D. G., maratne, W., Nanayakkara, N. P., Gurley, B. J., Gardner, S. F., Hubbard, dies by Hispanic patients: do they Yersiz, H., Goldstein, R. L., Ghobrial, Khan, I. A., and Sufka, K. J. M. A., Williams, D. K., Gentry, W. B., inform their physician? J. Am. Board M., and Busuttil, R. W. (2004). Ful- (2003). Anxiolytic properties of Khan, I. A., and Shah, A. (2005b). Fam. Med. 19, 566–578. minant liver failure due to usnic acid piper methysticum extract samples In vivo effects of goldenseal, kava Høyland, H. K. (2011). Use of Saint for weight loss. Am. J. Gastroenterol. and fractions in the chick social– kava, black cohosh, and valerian on John’s wort against mild depres- 5, 950–952. separation–stress procedure. Phy- human cytochrome P450 1A2, 2D6, sion. Tidsskr. Nor. Laegeforen. 131, Eichhorn, T., and Efferth, T. (2011). tother. Res. 17, 210–216. 2E1 and 3A4/5 phenotypes. Clin. 837–839. Pglycoprotein and its inhibition in Ferguson, C. S., and Tyndale, R. F. Pharmacol. Ther. 77, 415–426. Hsieh, M. J., Yen, Z. S., Chen, S. C., and tumors by phytochemicals derived (2011). Cytochrome P450 enzymes Hafner, V., Jäger, M., Matthée, A. K., Fang, C. C. (2008). Acute choliner- from Chinese herbal medicine. J. in the brain: emerging evidence of Ding, R., Burhenne, J., Haefeli, W. gic syndrome following ingestion of Ethnopharmacol. PMID: 21859398. biological significance. Trends Phar- E., and Mikus, G. (2009). Effect of contaminated herbal extract. Emerg. [Epub ahead of print]. macol. Sci. 32, 708–714. simultaneous induction and inhibi- Med. J. 25, 781–782. Emilio, L., Ghisalberti, E. L., Pennac- Ferrara, L., Montesano, D., and Sena- tion of CYP3A by St John’s wort and Hu, Z., Yang, X., Ho, P. C., Chan, S. Y., chio, M., and Alexander, E. (1998). tore, A. (2001). The distribution of ritonavir on CYP3A activity. Clin. Heng,P.W.,Chan,E.,Duan,W.,Koh, Survey of secondary plant metabo- minerals and flavonoids in the tea Pharmacol. Ther. 87, 191–196. H. L., and Zhou, S. (2005). Herb- lites with cardiovascular activity. plant Camellia sinensis. Farmaco 56, Hamann, G. L., Campbell, J. D., and drug interactions: a literature review. Pharm. Biol. 36, 237–279. 397–401. George, C. M. (2011). Warfarin- Drugs 65, 1239–1282. Emma, C. (2008). Lycopodium simili- Fugh-Berman, A. (2000). Herb-drug cranberry juice interaction. Ann. Huang, Z., Xiao, B., Wang, X., Li, Y., aplex-induced acute hepatitis: a case interactions. Lancet 355, 134–138. Pharmacother. 45, e17. and Deng, H. (2003). Betel nut

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 15 Fasinu et al. Herb–drug interactions

indulgence as a cause of epilepsy. Bauer, S., Scholler, G., Langheinrich, inhibitors from cranberry (Vac- pharmacodynamic response of Seizure 12, 406–408. M., and Roots, I. (2002). Decreased cinium macrocarpon) using human clopidogrel in hyporesponsive Huxtable, R. J., and Cooper, R. A. plasma levels of amitriptyline and its intestinal microsomes. Planta Med. volunteers and patients: increased (2000). “Pyrrolizidine alkaloids: metabolites on comedication with 77, 265–270. platelet inhibition by enhancement physicochemical correlates of an extract from St. John’s wort Kleiner, H. E., Xia, X., Sonoda, J., Zhang, of CYP3A4 metabolic activity. metabolism and toxicity,”in Natural (Hypericum perforatum). J. Clin. J., Pontius, E., Abey, J., Evans, R. M., J. Cardiovasc. Pharmacol. 57, and Selected Synthetic Toxins, eds A. Psychopharmacol. 22, 46–54. Moore, D. D., and DiGiovanni, J. 86–93. T. Tu and W. Gaffield (Washing- Kataya, H. H., Hamza, A. A., Ramadan, (2008). Effects of naturally occur- Lawvere, S., and Mahoney, M. C. (2005). ton: American Chemical Society), G. A., and Khasawneh, M. A. (2011). ring coumarins on hepatic drug- St John’s wort. Am. Fam. Physician 100–117. Effect of licorice extract on the com- metabolizing enzymes in mice. Tox- 72, 2249–2254. Iqbal, M., Sharma, S. D., Okazaki, Y., plications of diabetes nephropathy icol. Appl. Pharmacol. 232, 337–350. Leclercq, I. A., Farrell, G. C., Field, Fujisawa, M., and Okada, S. (2003). in rats. Drug Chem. Toxicol. 34, Klepser, T. B., Doucette, W. R., and J., Bell, D. R., Gonzalez, F. J., and Dietary supplementation of cur- 101–108. Horton, M. R. (2000). Assessment Robertson, G. R. (2000). CYP2E1 cumin enhances antioxidant and Katoh, M., Yoshioka, Y., Nakagawa, N., of patients’ perceptions and beliefs and CYP4A as microsomal cata- phase II metabolizing enzymes in and Yokoi, T. (2009). Effects of regarding herbal therapies. Pharma- lysts of lipid peroxides in murine ddY male mice: possible role in pro- Japanese herbal medicine, Kampo, cotherapy 20, 83–87. nonalcoholic steatohepatitis. J. Clin. tection against chemical carcinogen- on human UGT1A1 activity. Drug Knight, A. P., and Walter, R. G. Invest. 105, 1067–1075. esis and toxicity. Pharmacol. Toxicol. Metab. Pharmacokinet. 24, 226–234. (2002). “Plants affecting the car- Lee, J. Y., Duke, R. K., Tran, V. H., 92, 33–38. Kaufman, D., Kelly, J., Rosenberg, L., diovascular system,” in A Guide Hook, J. M., and Duke, C. C. (2006). Isbrucker, R. A., and Burdock, G. A. Anderson, T. E., and Mitchell, A. to Plant Poisoning of Animals in Hyperforin and its analogues inhibit (2006). Risk and safety assessment A. (2002). Recent patterns of med- North America, eds A. P. Knight CYP3A4 enzyme activity. Phyto- on the consumption of Licorice root ication use in the ambulatory adult and R. G. Walter. Available at: chemistry 67, 2550–6250. (Glycyrrhiza sp.), its extract and population of the United States. http://www.ivis.org/special_books/ Lewis, D. F. V. (2004). 57 varieties: the powder as a food ingredient, with JAMA 287, 37–44. Knight/chap2/ivis.pdf [accessed human cytochromes P450. Pharma- emphasis on the pharmacology and Kawahara, H., Mitani, Y., Nomura, M., November 05 2011]. cogenomics 5, 305–318. toxicology of glycyrrhizin. Regul. Nose, K., Yoneda, A., Hasegawa, Krishna, R., and Mayer, L. D. (2001). Lewis, J. H., Ahmed, M., Shobassy, A., Toxicol. Pharmacol. 46, 167–192. T., Kubota, A., and Fukuzawa, M. Modulation of P-glycoprotein and Palese, C. (2006). Drug-induced Isnard,B. C.,Deray,G.,Baumelou,A.,Le (2009). Impact of rikkunshito, an (PGP) mediated multidrug liver disease. Curr. Opin. Gastroen- Quintrec, M., and Vanherweghem, J. herbal medicine, on delayed gas- resistance (MDR) using chemosen- terol. 22, 223–233. L. (2004). Herbs and the kidney. Am. tric emptying in profoundly hand- sitizers: recent advances in the Li, M.,Andrew, M. A.,Wang, J., Salinger, J. Kidney Dis. 44, 1–11. icapped patients. Pediatr. Surg. Int. design of selective MDR modula- D. H., Vicini, P., Grady, R. W., Iwamoto, M., Kassahun, K., Troyer, M. 25, 987–990. tors. Curr. Med. Chem. Anticancer Phillips, B., Shen, D. D., and Ander- D., Hanley, W. D., Lu, P., Rhoton, A., Kennedy, J., Wang, C., and Wu, C. Agents 1, 163–174. son, G. D. (2009). Effects of cran- Petry, A. S., Ghosh, K., Mangin, E., (2008). Patient disclosure about Lai, M. N., Wang, S. M., Chen, P. C., berry juice on pharmacokinetics DeNoia, E. P., Wenning, L. A., Stone, herb and supplement use among Chen, Y. Y., and Wang, J. D. (2010). of beta-lactam antibiotics follow- J. A., Gottesdiener, K. M., and Wag- adults in the US. Evid. Based Com- Population-based case-control study ing oral administration. Antimicrob. ner,J. A. (2008). Lack of a pharmaco- plement. Alternat. Med. 5, 451–456. of Chinese herbal products contain- Agents Chemother. 53, 2725–2732. kinetic effect of raltegravir on mida- Kent, U. M., Aviram, M., Rosenblat, ing aristolochic acid and urinary Liang, Y., Xie, P., and Chan, K. (2004). zolam: in vitro/in vivo correlation. J. M., and Hollenberg, P. F. (2002). tract cancer risk. J. Natl. Cancer Inst. Quality control of herbal medicines. Clin. Pharmacol. 48, 209–214. The Licorice root derived isoflavan 102, 179–186. J. Chromatogr. 812, 53–70. Iwanaga, K., Hayashi, M., Hamahata, glabridin inhibits the activities of Laitinen, L., Takala, E., Vuorela, H., Liao, H., Ma, T., Li, Y., Chen, J. T., Y., Miyazaki, M., Shibano, M., human cytochrome P450S 3A4, 2B6, Vuorela, P., Kaukonen, A. M., and and Chang, Y. S. (2010). Concurrent Taniguchi, M., Baba, K., and Kakemi, and 2C9. Drug Metab. Dispos. 30, Marvola,M. (2007). Anthranoid lax- use of corticosteroids with Licorice- M. (2010). Furanocoumarin deriv- 709–715. ative influence the absorption of containing TCM preparations in atives in Kampo extract medicines Kessler, R. C., Davis, R. B., Foster, D. F., poorly permeable drugs in human Taiwan: a National Health Insurance inhibit cytochrome P450 3A4 and Van Rompay, M. I., Walters, E. E., intestinal cell culture model (Caco- Database Study. J. Altern. Comple- P-glycoprotein. Drug Metab. Dispos. Wilkey, S. A., Kaptchuk, T. J., and 2). Eur. J. Pharm. Biopharm. 66, ment. Med. 16, 539–544. 38, 1286–1294. Eisenberg, D. M. (2001). Long-term 135–145. Liu, C. X., Yi, X. L., Si, D. Y., Xiao, Izzo, A. A. (2005). Herb–drug interac- trends in the use of complementary Lala,L. G.,D’Mello,P.M.,and Naik,S. R. X. F., He, X., and Li, Y. Z. (2011). tions: an overview of the clinical evi- and alternative medical therapies in (2004). Pharmacokinetic and phar- Herb-drug interactions involving dence. Fundam. Clin. Pharmacol. 19, the United States. Ann. Intern. Med. macodynamic studies on interaction drug metabolizing enzymes and 1–16. 135, 262–268. of “Trikatu” with diclofenac sodium. transporters. Curr.DrugMetab.12, Izzo, A. A., and Ernst, E. (2009). Kim, B. H., Kim, K. P., Lim, K. S., J. Ethnopharmacol. 91, 277–280. 835–849. Interactions between herbal med- Kim, J. R., Yoon, S. H., Cho, J. Y., Lange, D. (2000). Conservation and Luyckx, V. A., and Naicker, S. (2008). icines and prescribed drugs: an Lee, Y. O., Lee, K. H., Jang, I. J., Sustainable use of Adonis Vernalis, Acute kidney injury associated with updated systematic review. Drugs 69, Shin, S. G., and Yu, K. S. (2010a). a Medicinal Plant in International the use of traditional medicines. Nat. 1777–1798. Influence of Ginkgo biloba extract Trade. Bonn: Federal Agency for Clin. Pract. Nephrol. 4, 664–671. Izzo, A. I., Sautebin, L., Rombola, L., on the pharmacodynamic effects Nature Conservation, 88. Ma, X. H., Zheng, C. J., Han, L. Y., and Capasso, F. (1997). The role and pharmacokinetic properties of Larsen, A. K., Escargueil, A. E., and Xie, B., Jia, J., Cao, Z. W., Li, Y. X., of constitutive nitric oxide synthase ticlopidine: an open-label, random- Skladanowski, A. (2000). Resistance and Chen, Y. Z. (2009). Synergistic in senna- and cascara-induced diar- ized, two-period, two-treatment, mechanisms associated with altered therapeutic actions of herbal ingre- rhoea in the rat. Eur. J. Pharmacol. two-sequence, single-dose crossover intracellular distribution of anti- dients and their mechanisms from 323, 93–97. study in healthy Korean male volun- cancer agents. Pharmacol. Ther. 85, molecular interaction and network Jha, V. (2010). Herbal medicines and teers. Clin. Ther. 32, 380–390. 217–229. perspectives. Drug Discov. Today 14, chronic kidney disease. Nephrology Kim, E., Sy-Cordero, A., Graf, T. N., Lau, W. C., Welch, T. D., Shields, 579–588. (Carlton) 15, 10–17. Brantley,S. J.,Paine,M. F.,and Ober- T., Rubenfire, M., Tantry, U. S., Madabushi, R., Frank, B., Drewelow, Johne, A., Schmider, J., Brockmöller, lies, N. H. (2010b). Isolation and and Gurbel, P. A. (2011). The B., Derendorf, H., and Butter- J., Stadelmann, A. M., Störmer, E., identification of intestinal CYP3A effect of St John’s wort on the weck, V. (2006). Hyperforin in

Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 | Article 69 | 16 Fasinu et al. Herb–drug interactions

St. John’s wort drug interac- T., Yoshikawa, M., Imazeki, F., and profile of GII purified from fenu- K., Neuvonen, P. J., and Olkkola, tions. Eur. J. Clin. Pharmacol. 62, Yokosuka, O. (2010). The tradi- greek (Trigonella foenum-graceum K. T. (2010). St John’s wort greatly 225–233. tional Japanese medicine rikkun- Linn.) seeds in diabetic animals. reduces the concentrations of oral Malati, C. Y., Robertson, S. M., shito increases the plasma level of Indian J. Exp. Biol. 48, 1119–1122. oxycodone. Eur. J. Pain 14, 854–859. Hunt, J. D., Chairez, C., Alfaro, ghrelin in humans and mice. J. Gas- Mu, Y., Zhang, J., Zhang, S., Zhou, H. Nishikawa, M., Ariyoshi, N., Kotani, A., R. M., Kovacs, J. A., and Pen- troenterol. 45, 300–307. H., Toma, D., Ren, S., Huang, L., Ishii, I., Nakamura, H., Nakasa, H., zak, S. R. (2011). Influence of Meijerman, I., Beijnen, J. H., and Schel- Yaramus, M., Baum, A., Venkatara- Ida, M., Nakamura, H., Kimura, N., Panax ginseng on cytochrome P450 lens, J. H. M. (2006). Herb-drug manan, R., and Xie, W. (2006). Kimura, M., Hasegawa, A., Kusu, (CYP)3A and P-glycoprotein (P- interactions in oncology: focus on Traditional Chinese medicines Wu F., Ohmori, S., Nakazawa, K., and gp) activity in healthy partici- mechanisms of induction. Oncolo- WeiZi(Schisandra chinensis Baill) Kitada, M. (2004). Effects of contin- pants. J. Clin. Pharmacol. doi: gist 11, 742–752. and Gan Cao (Glycyrrhiza uralensis uous ingestion of green tea or grape 10.1177/0091270011407194. [Epub Merino, G., Perez, M., Real, R., Egidom, Fisch) activate pregnane X receptor seed extracts on the pharmacoki- ahead of print]. E., Prieto, J. G., and Alvarez, A. and increase warfarin clearance in netics of midazolam. Drug Metab. Mannel, M. (2004). Drug interactions I. (2010). In vivo inhibition of rats. J. Pharmacol. Exp. Ther. 316, Pharmacokinet. 19, 280–289. with St John’s wort: mechanisms and BCRP/ABCG2 mediated transport 1369–1377. Nivitabishekam, S. N., Asad, M., and clinical implications. Drug Saf. 27, of nitrofurantoin by the isoflavones Mukhtar, H. M., Ansari, S. H., Bhat, Prasad, V. S. (2009). Pharmaco- 773–797. genistein and daidzein: a compara- Z. A., and Naved, T. (2006). Anti- dynamic interaction of Momordica Marchetti, S., Mazzanti, R., and Beij- tive study in BCRP1 mice. Pharm. hyperglycemic activity of Cyamopsis charantia with rosiglitazone in rats. nen, J. H. (2007). Concise review: Res. 27, 2098–2105. tetragonoloba. Beans on blood glu- Chem. Biol. Interact. 177, 247–253. clinical relevance of drug–drug and Methlie, P., Husebye, E., Hustad, cose levels in alloxan-induced dia- Norlin, M., and Wikvall, K. (2007). herb–drug interactions mediated S. S., Lien, E. A., and Løvås, betic rats. Pharm. Biol. 44, 10–13. Enzymes in the conversion of choles- by the ABC transporter ABCB1 K. (2011). Grapefruit juice and Munday, R., and Munday, C. M. (1999). terol into bile acids. Curr.Mol.Med. (MDR1, P-glycoprotein). Oncologist liquorice increase cortisol availabil- Low doses of diallyl disulfide, a com- 7, 199–218. 12, 927–941. ity in patients withAddison’s disease. pound derived from garlic, increase Nowack, R. (2008). Review article: Maridass,M.,and De Britto,A. J. (2008). Eur. J. Endocrinol. 165, 761–769. tissue activities of quinone reduc- cytochrome P450 enzyme, and Origins of plant derived medicines. Mitra, A. (2007). Anti-diabetic uses of tase and glutathione transferase in transport protein mediated herb- Ethnobotanical Leaflets 12, 373–387. some common herbs in tribal belts the gastrointestinal tract of the rat. drug interactions in renal trans- Markell, M. S. (2010). “Herbal reme- of Midnapur (West) district of Ben- Nutr. Cancer 34, 42–48. plant patients: grapefruit juice, St dies and the patient with chronic gal. EthnoMed 1, 37–45. Murakami, Y., Tanaka, T., Murakami, John’s wort – and beyond! Nephrol- kidney disease,” in Herbal Supple- Mochiki, E., Yanai, M., Ohno, T., and H., Tsujimoto, M., Ohtani, H., ogy (Carlton) 13, 337–347. ments: Efficacy, Toxicity, Interactions Kuwano,H. (2010). The effect of tra- and Sawada, Y. (2006). Pharmaco- Nutescu, E. A., Shapiro, N. L., Ibrahim, with Western Drugs, and Effects ditional Japanese medicine (Kampo) kinetic modelling of the interac- S., and West, P. (2006). Warfarin and on Clinical Laboratory Tests.doi: on gastrointestinal function. Surg. tion between St John’s wort and its interactions with foods,herbs and 10.1002/9780470910108.ch6 Today 40, 1105–1111. ciclosporin A. Br. J. Clin. Pharmacol. other dietary supplements. Expert Markowitz, J. S., DeVane, C. L., Chavin, Mohamed, M. E., and Frye, R. F. (2010). 61, 671–676. Opin. Drug Saf. 5, 433–451. K. D., Taylor, R. M., Ruan, Y., and Inhibition of intestinal and hepatic Nabekura, T., Yamaki, T., Hiroi, T., Ogbonnia, S., Adekunle, A. A., Bosa, M. Donovan, J. L. (2003a). Effects of glucuronidation of mycophenolic Ueno, K., and Kitagawa, S. (2010). K., and Enwuru,V. N. (2008). Evalu- garlic (Allium sativun L) supplemen- acid by Ginkgo biloba extract and Inhibition of anticancer drug efflux ation of acute and subacute toxicity tation on cytochrome P450 2D6 and flavonoids. Drug Metab. Dispos. 38, transporter P-glycoprotein by rose- of Alstonia congensis Engler (Apocy- 3A4 activity in healthy volunteers. 270–275. mary phytochemicals. Pharmacol. naceae) bark and Xylopia aethiopica Clin. Pharmacol. Ther. 74, 170–177. Mohamed, M. E., and Frye, R. F. Res. 61, 259–263. (Dunal) A. Rich (Annonaceae) fruits Markowitz, J. S., Donovan, J. L, DeVane, (2011a). Effects of herbal supple- Nagai, M., Fukamachi, T., Tsujimoto, mixtures used in the treatment C. L., Taylor, R. M., Ruan, Y., ments on drug glucuronidation. M., Ogura, K., Hiratsuka, A., Ohtani, of diabetes. Afr. J. Biotechnol. 7, Wang, J. S., and Chavin, K. D. Review of clinical, animal, and H., Hori, S., and Sawada, Y. (2009). 701–705. (2003b). Effect of St John’s wort in vitro studies. Planta Med. 77, Inhibitory effects of herbal extracts Okada, K., Shoda, J., Kano, M., Suzuki, on drug metabolism by induction 311–321. on the activity of human sulfotrans- S., Ohtake, N., Yamamoto, M., Taka- of cytochrome P450 3A4 Enzyme. Mohamed, M. E., and Frye, R. F. ferase isoform sulfotransferase 1A3 hashi, H., Utsunomiya, H., Oda, JAMA 290, 1500–1504. (2011b). Inhibitory effects of com- (SULT1A3). Biol. Pharm. Bull. 32, K., Sato, K., Watanabe, A., Ishii, Martignoni, M., Groothuis, G. M. M., monly used herbal extracts on UDP- 105–159. T., Itoh, K., Yamamoto, M., Yokoi, and de Kanter, R. (2006). Species glucuronosyltransferase 1A4, 1A6, Nakagawa, N., Katoh, M., Yoshioka, Y., T., Yoshizato, K., Sugiyama, Y., and differences between mouse, rat, dog, and 1A9 enzyme activities. Drug Nakajima, M., and Yokoi, T. (2009). Suzuki, H. (2007). Inchinkoto, a monkey and human CYP-mediated Metab. Dispos. 39, 1522–1528. Inhibitory effects of Kampo med- herbal medicine and its ingre- drug metabolism, inhibition and Mohammed, A. M. I., Jiang, X., icine on human UGT2B7 activ- dients dually exert Mrp2/MRP2- induction. Expert Opin. Drug Metab. Williams, K. M., Day, R. O., Roufo- ity. Drug Metab. Pharmacokinet. 24, mediated choleresis and Nrf2- Toxicol. 2, 875–894. galis, B. D., Liauw, W. S., Xu, H., and 490–499. mediated antioxidative action in rat Marx, J., Pretorius, E., Espag, W. J., and McLachlan, A. J. (2008). Pharma- Nebert, D. W., and Russell, D. W. liver. Am. J. Physiol. 292, G1450– Bester, M. J. (2005). Urginea san- codynamic interaction of warfarin (2002). Clinical importance of G1463. guinea: medicinal wonder or death with cranberry but not with garlic the cytochrome P450. Lancet 360, Oluwatuyi, M., Kaatz, G. W., and Gib- in disguise? Environ. Toxicol. Phar- in healthy subjects. Br. J. Pharmacol. 1155–1162. bons, S. (2004). Antibacterial and macol. 20, 26–34. 154, 1691–1700. Ni, W., Zhang, X., Wang, B., Chen, resistance modifying activity of Ros- Marzolini, C., Paus, E., Buclin, T., and Mok, D. K. W., and Chau, F. (2006). Y., Han, H., Fan, Y., Zhou, Y., Tai, marinus officinalis. Phytochemistry Kim, R. B. (2004). Polymorphisms Chemical information of Chinese G. (2010). Antitumor activities and 65, 3249–3254. in human MDR1 (P-glycoprotein): medicines: a challenge to chemist. immunomodulatory effects of gin- Ono, A. E., Owo, O. I., Itam, E. H., recent advances and clinical rele- Chemometrics Intell. Lab. Syst. 82, seng neutral polysaccharides in com- and Konya, R. S. (2000). Blood pres- vance. Clin. Pharmacol. Ther. 75, 210–217. bination with 5-fluorouracil. J. Med. sure depression by the fruit juice 13–33. Moorthy,R.,Prabhu,K. M.,and Murthy, Food 13, 270–277. of Carica papaya (L.) in renal and Matsumura, T., Arai, M., Yonemitsu, P. S. (2010). Mechanism of anti- Nieminen, T. H., Hagelberg, N. M., DOCA-induced hypertension in the Y., Maruoka, D., Tanaka, T., Suzuki, diabetic action, efficacy and safety Saari, T. I., Neuvonen, M., Laine, rat. Phytother. Res. 14, 235–239.

www.frontiersin.org April 2012 | Volume 3 | Article 69 | 17 Fasinu et al. Herb–drug interactions

Ono, S., Hatanaka, T., Hotta, H., Satoh, J. (2002). The effect of garlic sup- Savvidou, S., Goulis, J., Giavazis, I., in cytochrome P450 research. Drug T., Gonzalez, F. J., Tsutsui,M. (1996). plements on the pharmacokinetics Patsiaoura, K., Hytiroglou, P., Discov. Today 16, 793–799. Specificity of substrate and inhibitor of saquinavir. Clin. Infect. Dis. 34, and Arvanitakis, C. (2007). Herb- Sousa, S. A, Pascoa, H., Conceição, E. C., probes for cytochrome P450s: eval- 234–238. induced hepatitis by Teucrium Alves, S. F., Diniz, D. G. A., Paula, J. uation of in vitro metabolism using Qi, Q. H., Wang, J., Liang, G. G., polium L.: report of two cases and R., and Bara, M. T. F. (2011). Disso- cDNA-expressed human P450 and and Wu, X. Z. (2007). Da-Cheng- review of the literature. Eur. J. lution test of herbal medicines con- human liver microsomes. Xenobiot- Qi-Tang promotes the recovery Gastroenterol. Hepatol. 19, 507–511. taining Paullinia cupana: validation ica 26, 681–693. of gastrointestinal motility after Saxena, A. K., and Panbotra, B. of methods for quantification and Ozcakir, A., Sadikoglu, G., Bayram, abdominal surgery in humans. Dig. R. (2003). Herbal remedies: renal assessment of dissolution. Braz. J. N., Mazicioglu, M. M., Bilgel, N., Dis. Sci. 52, 1562–1570. tragedies. Swiss Med. Wkly. 133, Pharm. Sci. 47, 269–277. and Beyhan, I. (2007). Turkish gen- Quintieri, L., Palatini, P., Nassi, A., 188–189. Spinella, M., and Eaton, L. A. (2002). eral practitioners and complemen- Ruzza, P., and Floreani, M. (2008). Schoner, W. (2000). Ouabain, a new Hypomania induced by herbal and tary/alternative medicine. J. Altern. Flavonoids diosmetin and lute- steroid hormone of adrenal gland pharmaceutical psychotropic medi- Complement. Med. 13, 1007–1010. olin inhibit midazolam metabolism and hypothalamus. Exp. Clin. cines following mild traumatic brain Paine, M. F., Widmer, W. W., Pusek, by human liver microsomes and Endocrinol. Diabetes. 108, 449–454. injury. Brain Inj. 16, 359–367. S. N., Beavers, K. L, Criss, A. recombinant CYP3A4 and CYP3A5 Scott, G. N., and Elmer, G. W. (2002). Stadlbauer, V., Fickert, P., Lackner, C., B., Snyder, J., and Watkins, P. B. enzymes. Biochem. Pharmacol. 75, Update on natural product – drug Schmerlaib, J., Krisper, P., Trauner, (2008). Further characterization of 1426–1437. interactions. Am. J. Health Syst. M., and Stauber, R. E. (2005). Hepa- a furanocoumarin-free grapefruit Rannug, U., Agurell, E., Rannug, A., Pharm. 59, 339–347. totoxicity of NONI juice: report of juice on drug disposition: studies and Cederberg, H. (2006). Cer- Scott, M., Dinehart, S. M., and Henry, L. two cases. World J. Gastroenterol. 11, with cyclosporine. Am. J. Clin. Nutr. tain tryptophan photoproducts are (2005). Dietary supplements: altered 4758–6470. 87, 863–871. inhibitors of cytochrome P450- coagulation and effects on bruising. Stedman, C. (2002). Herbal hepatotox- Pal, D., and Mitra, A. K. (2006). MDR- dependent mutagenicity. Environ. Dermatol. Surg. 31, 819–836. icity. Semin. Liver Dis. 22, 195–206. and CYP3A4-mediated drug–herbal Mol. Mutagen. 20, 289–296. Sevior, D. K., Hokkanen, J., Tolonen, Steenkamp, V., and Stewart, M. (2005). interactions. Life Sci. 78, 2131–2145. Roberts, D., and Flanagan, P. (2011). A., Abass, K., Tursas, L., Pelkonen, Nephrotoxicity associated with Palombo, E. A. (2006). Phytochemicals Case report: cranberry juice and O., and Ahokas, J. T. (2010). Rapid exposure to plant toxins, with from traditional medicinal plants warfarin. Home Healthc. Nurse 29, screening of commercially available particular reference to Africa. Ther. used in the treatment of diarrhoea: 92–97. herbal products for the inhibition Drug Monit. 27, 270–277. modes of action and effects on Roby, C. A., Anderson, G., Kantor, E., of major human hepatic cytochrome Stewart, M. J., Steenkamp, V., van der intestinal function. Phytother. Res. Dryer, D. A., and Burstein, A. H. P450 enzymes using the N-in-one Merwe, S., Zuckerman, M., and 20, 717–724. (2000). St John’s wort: effect on cocktail. Xenobiotica 40, 2452–2454. Crowther, N. J. (2002). The cyto- Patanasethanont, D., Nagai, J., Yumoto, CYP3A4 activity. Clin. Pharmacol. Sheeja, K., Shihab, P. K., and Kut- toxic effects of a traditional Zulu R., Murakami, T., Sutthanut, K., Ther. 67, 451–457. tan, G. (2006). Antioxidant and remedy, irnpila (Callilepis laureola). Sripanidkulchai, B. O., Yenjai, C., Rogers, K. L., Grice, I. D., and anti-inflammatory activities of the Hum. Exp. Toxicol. 21, 643–647. and Takano, M. (2007). Effects of Griffiths, L. R. (2000). Inhibition plant Andrographis paniculata Nees. Suzuki,Y.,Ito,Y.,Konno,C.,and Furuya, Kaempferia parviflora extracts and of platelet aggregation and 5-HT Immunopharmacol. Immunotoxicol. T. (1991). Effects of tissue cultured their flavone constituents on P- release by extracts of Australian 28, 129–140. ginseng on gastric secretion and glycoprotein function. J. Pharm. Sci. plants used traditionally as headache Shekelle, P. G., Hardy, M. L., Morton, pepsin activity. YakugakuZasshi 111, 96, 223–233. treatments. Eur. J. Pharm. Sci. 9, S. C., Maglione, M., Mojica, W. A., 770–774. Patel, M., Bessong, P., and Liu, H. 355–363. Suttorp, M. J., Rhodes, S. L., Jungvig, Szakács, G., Váradi, A., Özvegy-Laczka, (2011). Traditional medicines, HIV, Rostami-Hodjegan,A.,and Tucker,G. T. L., and Gagné, J. (2003). Efficacy C., and Sarkadi, B. (2008). The and related infections: workshop 2C. (2007). Simulation and prediction of and safety of ephedra and ephedrine role of ABC transporters in drug Adv. Dent. Res. 23, 159–164. in vivo drug metabolism in human for weight loss and athletic perfor- absorption, distribution, metabo- Patsalos,P.,and Perucca,E. (2003). Clin- populations from in vitro data. Nat. mance. JAMA 289, 1537–1545. lism,excretion and toxicity (ADME– ically important drug interactions Rev. Drug Discov. 6, 140–148. Sheweita, S. A., Newairy, A. A., Man- Tox). Drug Discov. Today 13, in epilepsy: interactions between Routledge, P. A. (2008). The European sour, H. A., and Yousef,M. I. (2002). 379–393. antiepileptic drugs and other drugs. herbal medicines directive: could it Effect of some hypoglycemic herbs Szolomicki, S., Samochowiec, L., Wój- Lancet 2, 4734–4781. have saved the lives of Romeo and on the activity of phase I and II drug- cicki, J., and Drozdzik, M. (2000). Pavek, P., and Dvorak, Z. (2008). Juliet? Drug Saf. 31, 416–418. metabolizing enzymes in alloxan- The influence of active components Xenobiotic-induced transcriptional Saleem, T. S. M., Chetty, C. M., induced diabetic rats. Toxicology of Eleutherococcus senticosus on cel- regulation of xenobiotic metabo- Ramkanth, S., Rajan, V. S. T., Kumar, 174, 131–139. lular defence and physical fitness in lizing enzymes of the cytochrome K. M., and Gauthaman, K. (2010). Shi, Z., He, J., Yao, T., Chang, W., Zhao, man. Phytother. Res. 14, 30–35. P450 superfamily in human extra- Hepatoprotectiveherbs–areview. M. (2005). Simultaneous determi- Sztajnkrycer, M. D., Otten, E. J., Bond, hepatic tissues. Curr.DrugMetab.9, Int. J. Res. Pharm. Sci. 1, 1–5. nation of cryptotanshinone, tanshi- G. R., Lindsell, C. J., and Goetz, R. J. 129–143. Sanderson, J. T., Hordijk, J., Denison, none I and tanshinone IIA in tra- (2008). Mitigation of pennyroyal oil Perucca, E. (2006). Clinically relevant M. S., Springsteel, M. F., Nantz, M. ditional Chinese medicinal prepara- hepatotoxicity in the mouse. Acad. drug interactions with antiepileptic H., and van den Berg, M. (2004). tions containing Radix Salvia milti- Emerg. Med. 10, 1024–1028. drugs. Br. J. Clin. Pharmacol. 61, Induction and inhibition of aro- orrhiza by HPLC. J. Pharm. Biomed. Tachjian, A., Maria, V., and Jahangir, 246–255. matase (CYP19) activity by nat- Anal. 37, 481–486. A. (2010). Use of herbal products Pierard, S., Coche, J. C., Lanthier, P., ural and synthetic flavonoid com- Shukla, S., Zaher, H., Hartz, A., Bauer, and potential interactions in patients Dekoninck, X., Lanthier, N., Rahier, pounds in H295R human adreno- B., Ware, J. A., and Ambudkar, S. with cardiovascular diseases. J. Am. J., and Geubel, A. P. (2009). Severe cortical carcinoma cell. Toxicol. Sci. V. (2009). Curcumin inhibits the Coll. Cardiol. 9, 515–525. hepatitis associated with the use of 82, 70–79. activity of ABCG2/BCRP1, a mul- Taki, Y., Yokotani, K., Yamada, S., Shi- black cohosh: a report of two cases Sarris, J., LaPorte, E., and Schweitzer, tidrug resistance-linked ABC drug nozuka, K., Kubota, Y., Watanabe, and an advice for caution. Eur. J. I. (2011). Kava: a comprehensive transporter in mice. Pharm. Res. 26, Y., and Umegaki, K. (2012). Ginkgo Gastroenterol. Hepatol. 21, 941–945. review of efficacy, safety, and psy- 480–487. biloba extract attenuates warfarin- Piscitelli, S. C., Burstein, A. H., Welden, chopharmacology. Aust. N. Z. J. Psy- Singh, D., Kashyap,A., Pandey, R.V.,and mediated anticoagulation through N., Gallicano, K. D., and Falloon, chiatry 45, 27–35. Saini, K. S. (2011). Novel advances induction of hepatic cytochrome

Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 | Article 69 | 18 Fasinu et al. Herb–drug interactions

P450 enzymes by bilobalide in mice. Umehara, K. I., and Camenisch, G. (2009). An in vitro investigation of Yu, C. P., Wu, P. P., Hou, Y. C., Phytomedicine 19, 177–182. (2011). Novel in vitro-in vivo herbs traditionally used for kidney Lin, S. P., Tsai, S. Y., Chen, C. T., Tam, S. W., Worcel, M., and Wyllie, extrapolation (IVIVE) method to and urinary system disorders: poten- and Chao, P. D. (2011). Quercetin M. (2001). Yohimbine–aclin- predict hepatic organ clearance in tial therapeutic and toxic effects. and rutin reduced the bioavailabil- ical review. Pharmacol. Ther. 91, rat. Pharm. Res. 29, 603–617. Nephrology (Carlton) 14, 70–79. ity of cyclosporine from Neoral, an 215–243. van den Bout-van den Beukel, C. J., Wolf-Hall, C. (2010). “Fungal and immunosuppressant, through acti- Tamaki, H., Satoh, H., Hori, S., Ohtani, Hamza, O. J., Moshi, M. J., Matee, mushroom toxins,”in Pathogens and vating P-glycoprotein and CYP 3A4. H.,and Sawada,Y.(2010). Inhibitory M. I., Mikx, F., Burger, D. M., Koop- Toxins in Food: Challenges and Inter- J. Agric. Food Chem. 59, 4644–4648. effects of herbal extracts on breast mans, P. P., Verweij, P. E., Schoonen, ventions, eds V. K. Juneja and J. N. Zhang, X. (2002). Effect on gas- cancer resistance protein (BCRP) W. G., and van der Ven, A. J. (2008). Sofos (Washington,DC:ASM Press), trointestinal functions of Polygonum and structure-inhibitory potency Evaluation of cytotoxic, genotoxic 275–285. paleaceum. Zhong Yao Cai 25, relationship of isoflavonoids. Drug and CYP450 enzymatic competition Wood, M. J., Stewart, R. L., Merry, 192–193. Metab. Pharmacokinet. 25, 170–179. effects of Tanzanian plant extracts H., Johnstone, D. E., and Cox, J. Zhang, Z., and Wong, Y. N. (2005). Tang, J., Song, X., Zhu, M., and Zhang, traditionally used for treatment of L. (2003). Use of complementary Enzyme kinetics for clinically rel- J. (2009). Study on the pharmacoki- fungal infections. Basic Clin. Phar- and alternative medical therapies in evant CYP inhibition. Curr. Drug netic drug-drug interaction poten- macol. Toxicol. 102, 515–526. patients with cardiovascular disease. Metab. 6, 241–257. tial of Glycyrrhiza uralensis, a tradi- Van Roon, E. N., Flikweert, S., le Am.HeartJ.145, 806–812. Zhou, S., Lim, L. Y., and Chowbay, B. tional Chinese medicine, with lido- Comte, M., Langendijk, P. N., Kwee- Wu, C. L., Chiu, P. F., Yang, Y., Wen, (2004). Herbal modulation of P- caine in rats. Phytother. Res. 23, Zuiderwijk, W. J., Smits, P., and Y. K., Chiu, C. C., and Chang, C. glycoprotein. Drug Metab. Rev. 36, 603–607. Brouwers, J. R. (2005). Clinical rel- C. (2011). Sustained low-efficiency 57–104. Tang, J. C., Zhang, J. N., Wu, Y. T., evance of drug-drug interactions – daily diafiltration with hemoperfu- Zhou, S. F. (2008). Drugs behave as sub- and Li, Z. X. (2006). Effect of the a structured assessment procedure. sion as a therapy for severe star fruit strates, inhibitors and inducers of water extract and ethanol extract Drug Saf. 28, 1131–1139. intoxication: a report of two cases. human cytochrome P450 3A4. Curr. from traditional Chinese medicines Van Wyk, B., Van Oudtshoorn, B., and Ren. Fail. 33, 837–841. Drug Metab. 9, 310–322. Angelica sinensis (Oliv.) Diels, Ligus- Gericke, N. (2009). Medicinal Plants Wu, W. W., and Yeung, J. H. (2010). Zhu, B., Sun, Y., Yun, X., Han, S., ticum chuanxiong Hort and Rheum of South Africa, 2nd Edn. Pretoria: Inhibition of warfarin hydroxyla- Piao, M. L., Murata, Y., and Tada, palmatum L. on rat liver cytochrome Briza Publications, 336. tion by major tanshinones of Dan- M. (2004). Resistance imparted by P450 activity. Phytother. Res. 20, Vlachojannis, J., Cameron, M., and shen (Salvia miltiorrhiza) in the rat traditional Chinese medicines to 1046–1051. Chrubasik, S. (2011). Drug interac- in vitro and in vivo. Phytomedicine the acute change in glutamic pyru- Tannergren, C., Engman, H., Knutson, tions with St. John’s wort products. 17, 219–226. vic transaminase, alkaline phos- L., Hedeland, M, Bondesson, U., and Pharmacol. Res. 63, 254–256. Xu, L., Chen, Y., Pan, Y., Skiles, G. phatase and creatine kinase activi- Lennernäs, H. (2004). St John’s wort Waako, P. J., Smith, P., and Folb, P. L., and Shou, M. (2009). Prediction ties in rat blood caused by blood. decreases the bioavailability of R- I. (2005). In vitro interactions of of human drug-drug interactions Biosci. Biotechnol. Biochem. 68, and S-verapamil through induction Aspilia africana (Pers.) C. D. Adams, from time-dependent inactivation 1160–1163. of the first-pass metabolism. Clin. a traditional antimalarial medicinal of CYP3A4 in primary hepatocytes Ziment, I., and Tashkin, D. P. (2000). Pharmacol. Ther. 75, 298–309. plant, with artemisinin against Plas- using a population-based simulator. Alternative medicine for allergy and Taylor,L. (2000). Plants Based Drugs and modium falciparum. J. Ethnophar- Drug Metab. Dispos. 37, 2330–2339. asthma. J. Allergy Clin. Immunol. Medicines. Available at: http://www. macol. 102, 262–268. Yagmur, E., Piatkowski, A., Groger, A., 106, 603–614. rain-tree.com/plantdrugs.htm Wang, J. F., and Chou, K. C. (2010). Pallua, N., Gressner, A. M., and [accessed November 03, 2011]. Molecular modeling of cytochrome Kiefer, P. (2005). Bleeding compli- Conflict of Interest Statement: The Teschke, R. (2010). Kava hepatotoxicity: P450 and drug metabolism. Curr. cation under Gingko biloba medica- authors declare that the research was pathogenetic aspects and prospec- Drug Metab. 11, 342–346. tion. Am.J.Hematol.79, 343–344. conducted in the absence of any com- tive considerations. Liver Int. 30, Wang, J. F., Wei, D. Q., and Chou, K. C. Yao, W. X., and Jiang, M. X. (2002). mercial or financial relationships that 1270–1279. (2008). Drug candidates from tradi- Effects of tetrandrine on cardio- could be construed as a potential con- Tokita, Y., Yuzurihara, M., Sakaguchi, tional Chinese medicines. Curr. Top. vascular electrophysiologic prop- flict of interest. M., Satoh, K., and Kase, Y. (2007). Med. Chem. 8, 1656–6165. erties. Acta Pharmacol. Sin. 23, The pharmacological effects of Wang, Y., Shi, B., Cheng, Y., Xu, J., Jiang, 1069–1074. Received: 20 December 2011; accepted: Daikenchuto, a traditional herbal C. F., and Xie, W. F. (2009). Drug- Yap,K.Y.,See,C. S.,and Chan,A. (2010). 05 April 2012; published online: 30 April medicine, on delayed gastrointesti- induced liver disease: an 8-year study Clinically-relevant chemotherapy 2012. nal transit in rat postoperative ileus. of patients from one gastroentero- interactions with complementary Citation: Fasinu PS, Bouic PJ and J. Pharmacol. Sci. 104, 303–310. logical department. J. Dig. Dis. 10, and alternative medicines in patients Rosenkranz B (2012) An overview of the Tripathi, U. N., and Chandra, D. 195–200. with cancer. Recent Pat. Food Nutr. evidence and mechanisms of herb–drug (2010). Anti-hyperglycemic and Wilasrusmee, C., Kittur, S., Siddiqui, Agric. 2, 12–55. interactions. Front. Pharmacol. 3:69. doi: anti-oxidative effect of aqueous J., Bruch, D., Wilasrusmee, S., and Yin, O. Q. P., Tomlinson, B., and 10.3389/fphar.2012.00069 extract of Momordica charantia Kittur, D. S. (2002). In vitro Waye, M. M. Y. (2004). Pharma- This article was submitted to Frontiers pulp and Trigonella foenum graecum mmunomodulatory effects of ten cogenetics and herb-drug interac- in Pharmaceutical Medicine and Out- seed in alloxan-induced diabetic commonly used herbs on murine tions: experience with Ginkgo biloba comes Research, a specialty of Frontiers rats. Indian J. Biochem. Biophys. 47, lymphocytes. J. Altern. Complement. and omeprazole. Pharmacogenetics in Pharmacology. 227–233. Med. 8, 467–475. 14, 841–850. Copyright © 2012 Fasinu, Bouic and Ulbricht, C., Chao, W., Costa, D., Wills, R. B. H., Bone, K., and Morgan, Young, H. Y., Liao, J. C., Chang, Y. S, Rosenkranz. This is an open-access article Rusie-Seamon, E., Weissner, W., and M. (2000). Herbal products: active Luo, Y. L., Lu, M. C., and Peng, W. distributed under the terms of the Cre- Woods, J. (2008). Clinical evidence constituents, modes of action and H. (2006). Synergistic effect of gin- ative Commons Attribution Non Com- of herb-drug interactions: a system- quality control. Nutr. Res. Rev. 13, ger and nifedipine on human platelet mercial License, which permits non- atic review by the natural standard 47–77. aggregation: a study in hypertensive commercial use, distribution, and repro- research collaboration. Curr. Drug Wojcikowski, K., Wohlmuth, H., John- patients and normal volunteers. Am. duction in other forums, provided the Metab. 9, 1063–1120. son, D. W., Rolfe, M., and Gobe, G. J. Chin. Med. 34, 545–551. original authors and source are credited.

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