900112f m'tners nnPH/\RMACOLOGY

REVIEvlrAKrrsftoublished: 30 Aorll 2012

doi: 10.3389/fohar2012.00069

herl -drug interactionsPrus S. Fasinul , Patrick J. Bo,uic2,3 ancl Eernd Rosenkranzl *1 Divisi<tn of Pharmacology, Faculty of Health Sciences, University of Stellenbosch, CapeTown, South Afrtca

' Division of Medical Microbiology, Faculty of Health Sciences, Universitv of Stellenbosch, CapeTown, South Africas Syneta Life Sciences, Montague Garden:;, CapeTown, South Africa

Edited by:Javed (i. ljhaikh, Cardiff Research

Consortium: A CAPITA Group Ptc

Company,'lndia

Revieured by:Sirajudheen Anwar, University ofMessina, ltaly[)omenic<> Criscuolo, Genovax, ltalyfloge r \/e rbee ck, U n ive rsit6Catholique de Louvain, Belgium

*Conespondence:

Ilernd llosenkranz, Division ofP ha rmztcclogy, D epa rtment ofM edi ci n e, U n ivers itv of Ste I I e n bosch,PO Box 19063, Tygerberg, Cape Town

7505, Siouth Africae-ma i | : rose n kra nz@ su n a c. za

INTRODUCTIONllhere is; increasing consumptions ,c1'medicinal Lrerbs and herbalproducts globaliy, cutting acloss r;ocial and racial classes, as itis obs,elved bodr in developing and devr:lopecl countr:ies (Chcrrg

ct al., .1002; Ilorlt'k.'r, 2007; tr4 itra, 200 7). .Medicinal plants were thernajor agents for primary health care for many centuries beforethe aclvent of rnodern medicine (liLLeci;r et al., J.006). 'Iheir use

howerrer declined in most develoPed western countries duringthe larst century's industrialization ancL urbanization (t )gbo Lrr ia

et al., 2(l0B). In the past two deca<les however a new resurgencein medicinal plants consumption was observerl. According to the\MHO, about 70Vo of the world poprilatinn currre:ntly uses medic-inal h,:rbs as cornplementary or altelnative mr:dicine (\\rii1s ct al.,

2000). It is estirnated that over 40o/o of the adultAinerican popula-tion corLsume herbal products for one rnedical reason r:r the other

IJS also reveals that the consumpti,)n lla[tern of tradjtiona] med-ications has no significant gender or social difference ( h.essler eL al.,

J,001 ) , Consumption rate has also been particulariy exponential in

Despite [he lack of sufficient information on the safety of herbal products, their use as

alternative and/or conlplementary medicine is gk:bally popular.There is also an increasinginterest in medicinal herbs as precursor for pharnracological actives. Of serious concern is

the cr:ncurrent consumption of herbal products and conventional drugs. Herb-drug inter-;rc;tion (HDl) is the single most irnportant clinicirl consequence of this practice. Using a

structured assessrnent procedure, the evidence of HDI presents with varying degree ofr:linical significanc;e. While the poterntial for HDI for a number of herbal products is inferredfronr norr-hurnan studies, certain HDls are well established through human studies and

documentr:d case reports. Various mechanisms of pharmacokinetic HDI have been iden-tified and include the alteration in the gastrointestinal functions with consequent effectson clrug absorption; induction and inhibition of metabolic enzymes and transport proteins;irnd alteratior't of renal excretion ol'drugs and their metabolites. Due to the intrinsic phar-

rnac:ologic prr:perties of phytochemicals, pharmacodynamic HDls are also known to occur.The elfectsr could be synergistic, additive, and/or antagonistic. Poor reporting on the part ofpati13nts arrd l,he inability to promptly identify H Dl by health providers are identif ied as majorfactors limiting the extensive compilation of clinically relevant HDls. A general overviewirnd the signil'icance of pharmacokinetic and pharmacodynamic HDI are provided, detallingbasic mechanisrn, and nature of evidence available. An increased level of awareness of HDI

is necessary among health professionals and drug discovery scientists. With the increasingr'runrber of plant-sourced pharmacological actives, the potential for HDI should always be

irrise{:;sed in the non-clinical safety assessrrent phase of drug development process. Morer:linically relevant research is also required in this area as current information on HDI isinsufficient for clini<;al aoolications.

l(eyrarordE Herrts.drug interaction, traditional medicine, phytochemicals, transport proteins. cytochrome P450

9@)0),Austra1ia(IierrsriltssaLrc.ta1.,2()()4),aswellas Europe where the highest sales of herbal products have been

reported in Germany and France ((ia1,as.so ct a1., 2003). In Afiica,there is continuous addition to the list of medicinal herbs whileconsumption rate is also increasing. Between 60 and 85% nativeAfiir:ans use herbal medicine usually in combination (\,'an \\'1'kct al,, 2009).

The indications for herbal rernedies are diverse as they are

employed in the treatment of a wide range of diseases (Ernst,

2005). Studies have shown that 670/o of women use herbs forperimenopausal symptoms, 45% use it in pregnancy, and morethan 45o/o parents give herbal medications to their children forvarious meclical conditions (Emsr, 2004). Regulations in mostcountries do not require the demonstration of therapeutic effi-cacy, safety, or quality on the part of herbal remedies as most ofthem are promoted as natural and harmless (Ilomsl' et al.. 2004;

ItorLficrlge, 1008). It is pertinent however, that herbs are not free

from side effects as some have been shown to be toxic (I)c;ciga-

Recent study has shown

www.lf rontiersinr.org Aptil2Ol2lVolume 3 lArticle 69 | 1

Fasinu et al Herb-drug in teractions

habitual pattern of concomitant consumption of herbal and pre-scription medication. Ka rLfiran e t a1. ( 2002 ) reported that 14-160/o

of American adult population consume herbal supplements oftenconcomitantly with prescribed medications . Nso, 49.4o/o of Israeliconsumers of herbal remedies use them with prescription drugs(Giveon ct al , 200-1). This is significant bearing in mind that less

lhan 40o/o of patients disclose their herbal supplement usage totheir health care providers coupled with the fact that many physi-cians are unaware of the potential risks of herb-drug interactions(HDI; Iic'pser et al, 2000).

HDI is one of the most important clinical concerns in theconcomitant consumption of herbs and prescription drugs. Thenecessity of polypharmacy in the management of most diseases

further increases the risk of HDI in patients. The ability ofintestinal and hepatic CYP to metabolize numerous structurallyunrelated compounds, apart from being responsible for the poororal bioavailability of numerous drugs is responsible for the largenumber of documented drug--drug and drug-food interactions(Quintieri et al., 2008). This is more so, considering that oral drugdelivery is the most employed in the management of most disease

conditions in which case, drug interaction alters both bioavailabil-ity and pharmacokinetic disposition of the drug. This alterationand the resulting poor control of plasma drug concentrationswould particularly be of concern for drugs that have a narrowtherapeutic window or a precipitous dose-effect profile (Aungst,2000; i/c'rucca . 20tJ6). The risk of pharmacokinetic drug interac-tion poses two major extremity challenges - pharmacotoxicity andtreatment failure. The former can result from the inhibition of themetabolic enzymes responsible for the metabolism and clearance

of the drugs while the latter may be the consequence of enzymaticinduction leading to faster drug metabolism. This is in additionto the intrinsic pharmacodynamic actions of the herbal productsthemselves which may include potentiating, additive, antagonism,or neutralization effects.

Until recently, HDIwas often unsuspected byphysicians for sev-

eral reasons. Most trained physicians lack adequate knowledge onherbal drugs and their potentials for drug interactions (Clc.rllertet aJ.,2.005; Oz-cakir et a1.,2007; [rakcye arrcl Olr,'enrar1u,200ti);herbal products also vary considerably in compositions dependingon the source and package (l,iang ct al., 2004; Sousa ct al., 20 1 I );most patients do not consider it necessary to disclose their hel6iiconsumptions to physicians who themselves hardly inquire such(Ca.s.si.1v,2003; Hou,ell et al.,20f)a); Chao et al.,l00B;Kenned,v et al.,2008). Further challenges with herbal medications include scien-tific misidentification, product contamination and adulteration,mislabeling, active ingredient instability, variability in collectionprocedures, and failure ofdisclosure on the part ofpatients (RoLLl-

lata and Nace, 2000). A fairly recent systematic review by Izr,a

and l-lrnst i2009) on the interactions between medicinal herbs andprescribed medications provide some more details on these.

Herbal products are made of complex mixture of phar-macologically active phytochemicals (Lloli and Chau, 2006),most of which are secondary metabolites generated throughthe shikimate, acetate--malonate, and acetate-mevalonate path-ways. These constituents include phenolics (such as tannins,lignins, quinolones, and salicylates), phenolic glycosides (such as

flavonoids, cyanogens, and glucosinolates), terpenoids (such as

sesquiterpenes, steroids, carotenoids, saponins, and iridoids), alka-loids, peptides, polysaccharides (such as gums and mucitages),resins, and essential oils whichr often contain some of the afore-mentioned clasr;es of pliytochemicals (\\tills et al., 200(); \\'anget irl., 2008). This complexity increases the risk of clinicaI dru13

interactions.

AIM, SEAH|CFI STIIATEGY. AIIID SELECTION CRITERIAThe current reviert' v,'as therefore aimed at providing an ovt.rviewof kr.rown and recently leported HDI rvith intelest in the evi-dence available and the mechanism thereof. The revierv was

systematically con,Cucted by searching the databases of JMED-LINE, PUBMED, IlMBASll, arrd COCHI{AINE libraries fbr orig-inal resealches, arrd case reports on HDI using the fc,llowinllsearch terms or combinzrtions thereof: "drug-herb," "hertrdrug,""interactiorr," "c).tc,chtortre P4 50," "plant," "ext1act," "medi ci nal,""con comita nt aclrrinis tration," "herbal and orth odox medi<;ir-res. "Relevant search terms were ernployed to accommodate the vari-ous individual mediiciual h elbs ernployed in Africa, America, Asia,Europe, and Aui;trerlia. T.he rep,e11gfl interactions and their mech-anisms, wilh orthodox rnedications rvere searched and collated.Searches were not Lirnited by date or place ofpublications but ro

publications availarle in E,nglish larrguage.

RESULTS

CLINICAL PHIESENTATION OF HERB-DRUG INTERACTIONS

Clinical presentations of I-{DI varywidely depending on the herbsand the drugs r;oncerned, Typical clinical presentation ol HDIinclude the potentiation of the effects of oral corticosteroids in thepreserlce of liquorir:e (Glycyryll.i2a tloltrot ; I)oten-tiation ofu,arfalin effects withr resultant ,r.:sen.e

of garlic (Allium sa;tiyum.; Ilorrelli et rrl , 2007), dong quai (,Angel-

ica sinensis; Nrrtcscr,r et al., 2L)06), or danshen (Salyiamiltiorrhiza;Cban, 2001 ); decreased blood levels of nevirapine, amitrlprtyline,nifedipine, statins, digoxirr, ttreophylline, cyclosporine, rnjdazo-lam, and steroids iin patients concurrently consuming St Iohn'{rwort (SlW; Hypericum perforatum; Dc N1aar ot al.,2001; llr:nclcr..son et al.,2()0?; Johne irt aI..20()2; \,lirnnel,2004; tionelli andIz,zo, Z0(\9), decreased olal bioavailability of prednisolone in thepresence of the Chinese herbal product xiao-chai-hu tang (sho-saiko-to ; F u g1 r - B e r m an, 2 0 0 0 ) ; ginseng (Pan ax gin s en g) - :induceclmania in patients on a:ntidepressants (L,ngclborg ct al., -i001);

nation of neuroleptic drug,ls with betel t:ut (Areca catechu:; f[u.a"nt\

t:t al ,1.003; Coppola ancJ \4orrdola,2012); increased blood pres-sure induced by tricyclic antidepressant-yohimbe (Pausi.nrystalia

yohimbe) combination ('I increased phenytoinclearance and frequent i6zur,:s when combined with Alrrrcvedir:syrup shanl<hapusl rg other:clinical manifestati, I on themechanism of HDl..

EVIDENCE-BASED HDI STUDIES IIND CLINIGAT RELEVANCE

Herb-drug interactions lLave been reported through variorrs studl'techniques. While these reports usually give evidence of po1:entialinteractionr;, the level of evidence varies often failing to predictthe magnitude or ,sljnical sigrLificance of such H[DI. Apart fronL

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research Apnl 2012 | Volume 3 | Articl,r 69 | 2

f:asinu et al Herb-drug interactions

the sprecific limitations attributable to study methods employed,major draw-back in deducting relevant conclusions from reportedIHDI include misidentification and poor characterization of spec-imen, presence and nature of aduherants (some of which may beallerg,:ns), ynliations in study methodologies irncluding extractionprocedures, source location of herbs involved, seasonal variationin thr: phltochemical composition of herbal naterials, under-reportirrg and genetic factors involved in drug abr;orption, metab-olism, and dynamics. Thble 1 provides some limitations of thestudy rnethods.

Recently, structured assessment procedures are emerging in anattempt to provide levels of evidence for drug interactions. Inaddition to evidence ofinteraction, such assessment take into con-siderati,on clinical relevance ofthe potential adrrerse event resultingfrom the interaction, the modification- and patient-specific riskfactots, and disease conditions for which the interaction is impor-tant. ' deve.loped a system of hierarchicalevideirce-based structured assessment p.oi.,Jrr" of drug-druginteraction. This can be applicable to I{DI. This method particu-larly aLllows the extraction of HDIs that have been well establishedand t.hose that are merely inferred from certain phytochemicalchara,cteristics. A modified form of this method as presented inTable 2 is applied in this paper to provide the nature and level ofe-vidence for the HDIs mentioned.

MECHANISMS OF HERB-DRUG INTERACTIONS

The c,verlapping substrate specificity in the b,iotrans:formationalpathvrays of the physiologic systems is seen as the major reason fordrug-.drug, food-drug, and HDI (tr lalchctti et a1., 2007). The abil-ity of different chemical moieties to interact witth receptor sites andalter physiological environment can explain pharmacodynamicdrug interactions while pharmacokinetic interactions arise fromaltered absorption, interference in distribution pattern as well as

chang;esr and competition in the metabolic and excretorypathways

he major underlying mechanism of pharmacoki-drug-drug interaction, is either the induction or

inhibitipn of intestinal and hepatic metabolic enzymes particu-larly th4 CYP enzyme family, Additionally, similar effect on drugtranspofters and efflux proteins particularlythe p-glycoproteins inthe inteFtines is responsible in most other cases (N4eijerman et a[.,

2006; N<rwacli, 2008; Frrrkas et a1., 20I0). The pre-systemic activ-ity of CVP and efflux proteins often influence oral bioavailability,thus the modulating activity of co-administered herbal productshas been shown to result in pronounced reduction or increase inthe blogd levels of the affected drugs

Poteftial for in yivo drug interact d fromin vitro'istudies with liver enzymes. The correlation of in uitroresults lvith in viyo behavior has yielded reliable results in cer-

tain casps

or cllnlcal!

'Iucker,.20

Camcnisclwill be been in subsequent sections, were initially demonstratedthroug\ in vitro studies.

ducts with hepatic enzymes can

effects (r,an den llout-van dcnrn et al., 2009; r\sdaq and Inam-Kim et at., 2010a.) Specific liver

injury ipducible by phytochemical agents includes elevation ine andr fail-et a.1..

2002), l]iver cirrhosis (Lewis et al., 2006), fibrosis (Chirturi nnd

Farrell,12000), cholestasis (Chitturi and Farrc'll, 2008), zonal ordiffusivb hepatic necrosis (Savvitlou et al., 2007), and steato-sis (\\'ang et al., 2009). Mechanism of liver injury may includebioactivation of CYR oxidative stress, mitochondrial injury, andapoptosis (Crrllen, 2005).

Table 'l I Gomparison of study methods available llor HDl.

Report/$tudymethod Comments Advantages Limitations to clinical inferences

in vltro studies

/n vlvo studies

Case reprorts

lluman situdies

Deliberate investigations employing

metabolic enzymes, tissues, or

organs, e.9., CYP-transfer;terj cell

lines, hepatic subcellular fractions,

liver slices, intestinal tissues

lnvolves metabolic studies irr

mammals

Patients diagnosr.'d after history

taking, from HDI

Involves the use of human subjects

Provide information on potential

HDl, easy to perform, good for high

throughput screenings; Compared

1o in vivo animal studies, results are

closer to human if human

liver.based technologies are

emproyeo

Concentration and bioavailability of

active components are taken into

consideration

ldeal in providing information on HDI

The ideal study, providing directly

extrapolative data on interactions

Variations in experimental vs clinical concen-

trations; olh'et in vivo phenomena iike protein

binding and bioavailability are not accounted

for; poor reproducibility of results; poor corre-

lation to clinical situation

Results are often difficult to interpret due to

species variation; use of disproportionate and

non-physiologic dosages

Hardly discovered by physicians; infrequent

with poor statistical values in relation to each

medicinal herbs; under-reporting

Expensive; too stringent ethical considera-

tions; most subjects are healthy leaving out

the effects of pathologies on drug metabo-

lism; genetic variation in enzyme activity; poor

representative population

Apill 2012 | Volume 3 | Article 69 | 3www.f rontiersin.org

Fasinu et al Herb-drug interitctions

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

Level Description of evidence

2

3

A

Published theoretical proof or expert opinion on the possibility of HDI due to certain factors including the presence of known Inreraclngphytochemicals in the herbs, structure activity relationshib

Pharmacodynamic and/or pharmacokinetic animal studieS; in vltro studies with a limited predictive value for human ln viyo situation

Well documented, published case reports with the absen'ce of other explaining factors

Controlled, published interaction studies in patients or heblthy volunteers with surrogate or r:linically relevant endpoint

Induction and inhibition of netabolic enzymes

The CYP superfamily is generally involved in oxidative, pdroxida-tive, and reductive biotransformation ofxenobiotics and €ndoge-nous compoundsis conventionallynucleotide sequence homology (Fasinu et al., 2012). Tdere is ahigh degree of substrate specificity among the various families.CYP belonging to the families l, 2, and 3 are principally irrvolvedin xenobiotic metabolism while others play a major rolb in theformation and elimination of endogenorr, .o-poorrdslsuch as

hormones, bile acids, and fatty acids (Norlin ancl Wikvall, 2007;

Amachel, 2010), The most important CYP subfamilies fespon-sible for drug metabolism in humans are lA2, 2A6,2C9,2C19,2D6,281,3A4, and 3A5 (Ono et al.. 1996; \fang and Chcru,

201 0).CYPIA1 and 1A2 are the two major members of thelhuman

CYPIA subfamily. CYP lAl is mainly expressed in extralhepatictissues such as the kidney, the intestines, and the lungs whileCYP 1A2 constitutes about 150/o of total hepatic CYP (Vtaltignon i

et al., 2006). CYP2B6 is involved in drug metabolism while mostother members of the CYP2B subfamily play less significarit meta-bolic roles (Paveli and Dvorak, 2003). The subfamily Zb is thesecond most abundant CYP after 34' representin g over 20d/o of thetotal CYP present in the human liver. It comprises threb activemembers: 2C8, 2C9, and 2Cl9 all of which are also ihvolvedin the metabolism of some endogenous cotrrpounds includingretinol and retinoic acid (Lc'u'is, 2004). Few clinically relevantdrugs including paracetamol, chlorzoxazone, and enflurane are

metabolized by CYP2El, the most active of the 2E subfamilyCYP3A subfamily constitutes oier 40o/o

of the total CYP in the human body (although the levels mayvary 4O-fold among individuals) with CYP3A4 being tlie mostabundant of all isoforms higtrly expressed in the liver hnd theintestines and participates in the metabolisrn of about'half ofdrugs in use today (Irereusoi.r and 'I1'ndale, 2011; Singh et al.,201 1). The specificity and selectivity of substrates and inhibitorsfor these enzymes are particularly useful in pharmacokinetic andtoxicological studies.

Induction is the increase in intestinal and hepatic bnzymeactivity as a result of increased mRNA transcription leading toprotein levels higher than normal physiologic values. Wllen thishappens, there is a corresponding increase in the rate of drugmetabolism affecting both the oral bioavailability and the sys-

temic disposition. In the formulation and dosage design'of oralmedications, allowance is often made for pre-systemic rhetabo-Iism in order to achieve predictable systemic bioavailability. Adisruption in this balance can result in significant changes ih blood

concentrations of the drugs. Certain herbal products have beenshown to be capable of inducing CYP. Concomitant administra-tion of enzyme-inducing herbal products and prescription drugscan therefore result in sub-therapeutic plasma levels of ttLe latterwith therapeutic failure as a possible clinical consequence.

Apart from enzyme induction, herbal products can also inhibitenzyme activities. 'Ihe inhibition of CYP and other metabolicenzymes is r-Lsually competitive with instantaneous and inhibitorconcentration-depend.ent effects (Zhang and \t'ong, 2005), Mostinhibitors are also substrates of CYP his phenom-enon alters pharma.cokinetic profile signilicantly.As a result of the suppression of the anticipated pre-systemicintestinal and hepatic metabolism, unusually high plasma levelsof xenobiotics are observed. 'Ioxic manifestation could be theultimate effbct of this observation. An equally clinically innpor-tant consequ.ence of en4mre inhibition is drug accumulatio:n dueto subdued hepatic clearance. These effects will be of parrticu-Iar concerns in drugs with narrow therapeutic window or steepdose-response profiles.

St John's wort is; one of the most widely used herbal antide-pressants It is a

potent rn ,Cura-

tion and route of adminisl,ration, it may induce or inhibit otherCYP isozymes and J?-gp (Roby et al., 2000; Marlcolr'itz er al.,2003b; 'lhnner:glr.11 et al., 200,+; lv{adabushi et a1., 2006). ,Stud-ies from case reports indicate that, due to its inducing effectson CYP3A4, it significantly recluces the plasma levels of CYP3A4substrates irrcludingJ cyclosporine, simvastatin, indinavir, warfarin,amitriptyline, tacro.lirnus, oxycodone, and nevirapine (FIender.sonet al., 2002; ft rhne et al., 2002; Nicminen et al., 20 1 0; Vlachoj annisct al.,20ll). It has also been r:eported that the alteration in theblood serum concelttration of ryclosporine due to SIW has lled toorgan rejection in patients (E,rnst, 2002; Xzlurakami et a1., 2006).Reports of breakthrrrugh blto interaction between SIW antl oral contraceptives have also beendocumented 'llhe group of drugs with the highestpotential for clinicaLlly significant pharmacokinetic drug interac-tion with SfW is the antidepressants as SI\{ itself is consumed bypatients with depression. Its concomitant use with SSRI like ser-traline and paroxetine has been reported to result in symp'tomsof central serotonergic syn<lrome (Rarbenel et al., 2000; Dannarti,2002; Spinella autl Eaton, ?002; Birrres et aI.,2003; Bonetto et al.,2007).Ir has also tleen said to increase the incidence ofhypo-glycemia in patientr; on tolbutamide without apparent alterationin the phar:macokinetic profile of tolbutamide (tr4annel, 200'1).It also inhibits the production of SN-38, an actiirinotecan, in cancer patients.

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcdmes Research Aptil2012 |Volume 3 |Artirrle 69 |4

Fasinu et al. Herb-drug Interactrons

Arnitriptyline is a substrate to both CYP3A4 and intestinal P-

gp. The risk of therapeutic failure is thus high due to induction ofCYP3A4-dependent metabolism activities resnlting in poor oralbioavailability. In a study by Joh rrc e t ai. (2002), a 2106 decrease inthe areeL under the plasma concentration-tirne curve of amitripty-line u'a:; observed in l2 depressed patierrts who were co ncomitantlyadministered with extracts of SfW and amitriptyline lior 2 weeks.

Other CYP and P-gp substrates whose pharrnacokinetic pro-file h,ave been reportedly altered by SIW inc.luclLe anticoagulantslike phr:nprocoumon and warfarin; antihistarnines like fexofena-dine; arLtiretroviral drugs including protease inhibitorr; and reversetransr:riptase inhibitors; hypoglycemic agents such as tolbutamide;immunosuppressants like cyclosporine, tacrolimus, and mycophe-nolic acid; anticon"'ulsants snch as carbamazep,ine; anti-cancerlikeirinotecan; bronchodilators like theophl,lline; antitussive like dex-tromr:thorphan; cardiovascular drugs like statins, digoxin, anddihydropyridine calcium channel blocJ<ers; oral contraceptives;opiat,:s like methadone and loperarrride; arrd benz:odiazepines

inclu,:ling alprazolam and midazolam. (GleesorL et a1., 2001; Dict al., 2008; Iloio ct al , 2011). Following a single dose adminis-tration of 300 mg standardized extracts of S;JW containing 5%

hypelfcrrin in humans, a rnaxirrLum plasrn'a r:oncentration of0.17-0.5 pM hyperforin yielding a [1]/Ki >.(t.22, in ilvo extrap-olaticrn suggests a high possibility of in yilo pharmacokineticdrug interaction (Aglosi et al., 2000). lJrav eL rl. (,1002) con-firmed through animal studies that SJV/ moclulates various CYP

enzymes. I)rcsser et a1 (2007) dernonstrated that SIM is capable

ofinducing CYP3A4 in healthy subjects through the observationof in,:reased urinary clearance of midazolarrr" Thus animal andhuman studies further confirm SJW as contairring both inhibitoryand irnilucing constituents on various CYP isorzyrnes. llhese effects

may rlepend on dosage and duration of administration, and mayalso be species- and tissue-specific. M4rile the i:ndividual phyto-chemical constituents of SJW hav: eli,;ited varying effects on themetabolic activity of the CYP isozymes, whole extracl.s and majorconstituents especially hlperforin have been reported to inhibitthe nre tabolic activities of CYP 1 42, zc\;t, 2C,19, 2D 6, and 3 A4 viain yil:rc, sludies and in yi"to stu.di.e:s (l,ec et aJ., ,2006; NlaclabLrshi

ct al., 2006; Hokkancn r:t aL., 201l).Gtintkgo biloba have been reported to induce CYP 2C19-

depe:rd.ent omeprazole metabolism in healthy hurnan subjects(Yin t:t al., 2004). l']iscitelli ct al. ( 2002 ) in a garl ic- saqu inavir inter-actiorr study reported 51olo decrease in saquinavir oral bioavail-ability,caused by the presence ofgarlic and attributable to garlic-indur:e,l CYP3A4 induction. Its elTects on the warfarin pharma-cokinrel.ic has also been reported in animal models ('ta[<i et al.,

20t2"t.

Althou.gh grapefruit juice is not consumed f<rr medicinal pur-poses;, the discovery of the inhitritory activity of its flavonoidconte:nls on CYP has led to further researches; in medicinal herbswhich have revealed HDI potentials in flavonoid-r:ontaining herbalremedies (Choi and Bur'rn, 200rj; Palonrlro, 2(X)6; Pain,e et al., 11008;

QrLinrir:ri ct al., 200tt; Ahrarcz er al., 2(l | ()). A rdaled CYP inhibitoris roterLone. By interfering with the el:ctron transfer of the hemeiron, rotenone, a naturally occurrirng ph'ftochemical found in sev-

eral pleLnts such as the jicama vine planl. is Lnown to inhibit CYP

activity (iiandersoLr et al , 2004). Resveratrol, a natural polymer,

and tryptophan, an amino acid have been documented as potentCYP inhibitors (l{xnnug et a1., 2006). Some herbal medicationsand their phytochernical constituents capable of interacting withCYP are presented in Table 3. A more detailed involvement of CYP

in HDI is detailed in some recently published reviews (T)elgocla

ancl \'\restlal<e, 2004; Pd, and N'litra, 2006; Corclia ancl Stecnl<anrp,

l0l 1; Liu d al,,20Lt).Phase II metabolic enzymes including uridine diphosphoglu-

curonosyl transferase (UGT), N-acetyl transferase (NAT), glu-tathione S-transfelase (GST), and sulfotransferase (ST) catalyze

the attachment of polar and ionizable groups to phase I metabo-Iites aiding their elimination. While cytochrome P450-mediatedHDI have been extensively investigated in various studies, theeffects ofherbal extracts on phase II enzymes have not been ade-

quately studied. However, there is sufficient evidence in literatureto suggest the potentials of phase II enzymes to induce clinicallysignificant HDI.

In a study carried out in rat models by lihen,clta ct al. (2002),

extracts of hypoglycemic herbs, Qtmbopogon proximus, Zygophyl-Ium. coccineum, and Lupinus albus redtcedthe activity of GST andGSH. Curcumin, from Curcuma longa, anherbal antioxidant withanti-inflammatory and antitumor properties increased the activ-ity of GST and quinone reductase in the ddY mice liver (lc1bai

et al., 200-i). Valerian, an herbal sleeping aid has also demon-strated the potential of inducing HDI through the inhibition ofUGT. Up to 87o/o of inhibition of UGT activity by valerian extract

was reported in an in rzlfro study utilizing estradiol and morphineas probe substrate (Alkhar11, ancl Ft'1'e, 2007). Kampo, a tradi-tional fapanese medicine made of a mixture of several medicinalherbs has shown inhibitory effects on some phase II enzymes. Inan in vitro study by Nal<agau'ir ct al. (2009), nine out of 5lcom-ponents of kampo medicine elicited more than 50olo inhibitionof IJGT2BT-mediated morphine 3-glucuronidation. In the same

study, extracts of kanzo (Glycyrrhizae radix), daio (Rhei rhizoma),

and keihi (Cinnamomi cortex) elicited more than 80% inhibitionof morphine AZT glucuronidation. This result agrees with Katoh

ct al. (2009) who carried out similar studies on rhei, keihi, ando gon ( S cut ell ar iae ra dix).

Apart frorn the well-known effects on Ginkgo biloba on CYP

enzymes as illustrated earlier, its extracts have demonstratedpotent inhibition of mycophenolic acid glucuronidation inves-tigated in human liver and intestinal microsomes (tr1oh;rmcd and

Irrr.e, ,0 I 0).

) n a study to investigate the influence of 1 8 herbal rernedies onthe activity of human recombinant sulfotransferase 1A1) employ-ing dopamine and ritodrine as substrates, extracts of grape seed,

milk thistle, gymnema, SJW, ginkgo leaf, banaba, rafuma, andpeanut seed coat showed potent inhibition with IC5s values lowerthan putative gastrointestinal concentration (Nagai ct irl., 2009).

Similarly, i\loharncr{ ar.Ld }:rr.e (201 tb) reported the inhibition ofUGTIA4 by green tea derived epigallocatechin gallate; UGT 1A6

and UGTIAg by milk thistle; UG'I 14'6 by saw palmetto; andUGT 1A9 by cranberry. A recent publication presents evidence ofpotential HDI mediated by UGT (ithhamed arcl Fr'1'e, 201 1a).

Certain phytochemicals including coumarin, limettin,auraptene, angelicin, bergamottin, imperatorin, andisopimpinellin have also been reported to be capable of inducing

www:frontiersin.org Ap(\l 2012 | Volume 3 I Article 69 | 5

Herb-drug inte16ctions

oa*0ooou!

i 6 G 9. €d i''

E 3 e=^ P..?: ;-i -s:-59 aEci FR; rRfi.E EtH€ '.:f ErBe; :i-" E;I :qEeE ;5:s :l3 ^ i € e16 I.qr,m;-06: 'oP-';-=id::5o;:E? !o;: o=c6iJ.6(J'sz euVbSrS

-co --GGa=oO^oa

iiF=ts-.(6-JNh":OtrL-O.ucvE-^otiS

--'wN- ; P-: -

6;9;!QX;-=t:rios3E-d-6i-.ER:^-A:*-OOo=;-x-__o

OOX'UJO:NC!;5>S

.E.=NSO_eE: s { -

oiEaEmcf; ?€rE €e$ H $ I Ei c €(J o -ar N @ F a-; -F.oooyl* Xi€E6E9 3F €Fm piE6S{6;' N; =E; >sF=>:> >: X:QUL:QVOVVAV6

pP?FXo-;.\

-Ya;(AFqH x €€i\ c - - l

i^6-'xE; Z E*edSo O 5 o

EPIie5:06;AGy o- !2 --' o_.++ (J >'"- -ci d (J

* t:ER @ FI Et FgN ki N c

^.\lo^-i ;sF 3 fi €Y .=!$ g- t .c-

L - 2- a)-!: e? F-^-: X;+x E

F9:9R Tt.r: o

;63RH-H';i5 5Y_OF-;\6;\):'FF!*EP5:>X:;€- €o;HER3E3Si E8

=;n Y'IO-

EEeOij>.otroo!N-oh<.9 s;;*

OO

F6o=P

'--N

t5 al

uicPo

e,"E3-9o6i6X{!+ E E >- X9FE EPF * F€.=6E €ioq E 'Yo'- q6E_bP x>9 ES*E6 EO,9 E FF

'-'aEf

o;E.!

PF b >!> : x>o+;

oSq)YOd.eSxo\'=RON:REi5idpx

es+3\oS6.i-x€FPfi+qi{ts$$ IERFPTSi x's I\ HsH.eR9*&{Sd*6r6f

I-'^oavEo!Q)eRisop6a?<E=e:9doEEE;*}Ep,8Hg€thn'iZ'E!EE*q3so.!uiioooovia,

a

xo^

o

a

i06()A(9

Aptil 2012 l Volume 3 | Article 69 | 6ResearchFrontiers in Pharmacology I Pharmaceutical Medicine and Ou

o

oeocc

IIJJ

ooflot:e,

tr

eoo

tt!

o

tr

.9 .9FE;6

=L6gE.E

q

o

oc

GE

q)

(,

fl

ooth

(!

s3ooo.EEESo=EE

Fasinu et al

o

o

xEo

€4C)t.tsIg{,

o

3o.Y6of

octollo(,

o('o

t:

Fasinu et al Herb-drug interactions

hepal:ic GST activities (Klelnc'r et a1., 2008), 'vVhile the clinicalsignilicance of these findings are yet to be determined, it is note-worthy that phase II metabolic enzymes may play significant rolesin HDIs.

lnhibtition and induction of transport and efflux proteinsThe llTP-binding cassette (ABC) family of druLg transporters plays

signilicant roles in the absorption, dir;tribution, and eliminationof drugs. P-gp, the most studied rnember of this family is a 170-

kDa;plasma glycoprotein encoded by the hurman MDRI gene. Itis constitutively expressed in a number of body tissues and con-centrated on the apical epithelial surfaces of the bile canaliculi ofthe liver, the proximal tubules of the kiclneys, the pancreatic duc-tal celk;, the columnar mucosal cells of the smali intestine, colon,and the adrenal glands (Ntalzoliui ct al., 20()4; L)egortel et al,,

2012'.l.It is actively involved in drug absorption and eliminationfrom the intestines the liver; kidneys, and the brain. Specificallythese proteins are involved in the processes of hepatotriliary, directinteslinal, and urinary excretion of dnrgs arrd their metabolites(Szak.{cs er al,, 2008). Thus, the modulation of P-gp, or competi-tive affinity as substrates for its binding sites by co-administeredherbs presents a potential for alteration in tlre pharmacokineticprofiJle of the drug.

Pharmacokinetic interaction occurs when herbal drugs inhibitor decrease the normal activity level of drug trransporters througha cornpetitive or non-competitive mechanism. Interactions can

also ,cccur through the induction of transp()rt proleins via theincrease of the mRNA of the relevant protein. Studies have iden-tified a number of clinically important P-gp inhibitors includingphytochemicals - flavonoids, furanocoumari:ns, reserpine, quini-dine, yohimbine, vincristine, vinblastine among others (Krishnaauci ivlayer',2001; Zhou et a1.,2004; PataLrasethanont et a1.,2007;

hvanaga et a'l.,2010; Eichhorn and F,ilerth,2011; Yu et a1.,201 1).

Bolrel let al. (1994) reported that mobile ionophores such as

valinor.irycin, nonactin, nigericin, monensin, calcimycin, and lasa-

locid i4hibit the efflux of anthracycline by P-gp whereas channel-

forming ionophores such as gramicidin do not (Lalsen et a1.,

2000). A number of herbal products which interactwith CYP also

have sifnilar effects on transport proteins (Table 3). The trans-port pqoteins are actively involved in the pharmacokinetics ofanti-capcer drugs and account for one of the well-known mecha-nisms qf multiple resistance of cancerous cells to chemotherapeu-

tic age4ts (I3ebarvy and S2e,2008; Ilosch,2008; He et a1,,2011).The influence of some herbs on transport proteins is presented inTable t\. Clinically relevant interactions between herbal medicineand chgmotherapeutic agents are detailed in a recent review byl'apet al. (201 0).

zymes andion ofcon-of mecha-

nisms. Changes in the gastrointestinal pH and other biochemicalfactors, can alter dissolution properties and the absorption ofpH-deXrendent drugs such as ketoconazole and itraconazole. Com-plexatign and chelation, leading to the formation of insolublecomple,xes and competition at the sites of absorption especially

icationi significant alteration in the absorption of the latter has

been rgported due to decreased GI transit time (Fugh-llerlnatl,2000).

i

Table 4 | Influence of herbal products on transpon proteins.

Drug transporter Anti-cancer substrates Interacting herbal products Reference

P-glycoprotein

(ABCB-1, MDR-l)

MRP-1 (ABCC-I)

MRP-2 (ABCC-2)

BCRP (ABCG-2,

MXR)

Actinomycin D, daunorubicin, docetaxel,

doxorubicin, etoposide, irinc,tecan, rnitoxantrone,

paclitaxel, teniposide, topotecan, vinblastine,

vincristine, tamoxifen, mitornycin C, tipifarnib,

epirubicin, bisantrene

Etoposide, teniposide, vincristine, virrblastine,

doxorubicin, daunorubicin, epirubicin, idarubicin,

topotecan, irinotec€rn, mitoxantrone, chlorambucil,

methotrexate, mel6rhalan

SN-38G (metabolite of irinol:ecan), methotrexate,

sulfinpyrazone, vinLrlastine

9-Aminocamptothecin, daunorubicin, epirubicin,

etoposide, lurtotecan, mito),lan[rone, SN-38,

roporecan

Fosmarinus officinalis

Curcuma longa

I nchin-ko-to

Flavonoid-containing herbs such as

Glycine max (soybean), Gymnema

sylve stre, and C i m ic if uga race m osa

(black cohosh)

oluwatuyr et al. (2004),

Itlabekura et al. t2010)

Shukla et al. (2009)

Okada et al l2o07l

Meririo ei a. 1.2010),

Tamaki et al (2010)

LE, le',tel of evidence.

ABC, ATP-binding cassette; BCRE breast cancer resistan,ce protein; MDR, multidrug resistance gene; MRP multidrug resistance-associated protein; MXR, mitoxantrone

res i stil nce-associated prote i n,

April2012 |Volume 3 |Article 69 |7

Fasinu et al Herb-drug interactions

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

Medicinal plants Briel description Mechanism LE Reference

Aristolochia fangchi

Djenkol bean (Pithecellobium lobatum)

lmpila lCa I I i I e p i s I a u reo I al

Wild mushrooms

Licorice root lGlvcyrrhiza glabral

Noni fruit (Morinda citrifolial, alfalfa(Medicago saliva), Dandelion lTaraxacum

officinale), horsetail (Equisetum arvense),

stinging nettle (Urtica dioical

Rhubarb \Rheum officinalel

Star fruit (Averrhoa carambolal

Uva ursi lArctostaphylos uva ursi),

goldenrod lSolidago virgaureal, dandelion(Taraxacum officinale), juniper beny(J un ipe rus commu n is), horsetail(Equisetum arvense), lovage root

I Levi sti c u m off i ci n a I el, par sley

lPetroselinum crispuml, asparagus root

lAspa rag u s off i c i na I i sl, sti n ging nettle leal

lUrtica dioical, alfalla (Medicago sativaJ

Chinese slimming herbal

remedy

Pungent smelling edible fruit,

used for medicinal purposes

in Africa

Popular South African

medicinal herb

Widely consumed in Africa

Leguminous herb native to

Europe and Asia, root and

extracts are used in chronic

hepatitis and other ailments

These plants and their

extracts are used variously in

traditional medicine, and have

been shown to contain very

high potassium levels

Used as laxative

A tree popular in Southeast

Asia and South America

employed traditionally as

antioxidant and antimicrobial\/^.i^,,^ ^l^^+^ ,,^^l ^^VOI IUUJ PIdI ILJ UDUU OJ

diu retics

Aristolochic acid conternl forrns; DNA

adducts in renal tissues leading toextensive loss of cortical tubules

Contains nephrotoxic djenkolic acid

Causes damage to the proxitnal convoluted

tubules and tlre loop c,f henle, shown to be

hepatotoxrc

Some specie:s especially Cortinarius

contains nephrotoxic orellanine

Contains glycynhizic acid whose

metabolite, glvcyrrhetrnic acid inhibits renal

1 1-hydroxysteroid dehydrogenase leading to

a pseudoaldosteronelike

effect - accurnulation of cortisol in thekidney, stimulation of lhe aldosterone

receptors in cells of the cortic€tl leading to

increased BP sodium retentiorr, and

hypokalemia. This rna\,' poten tlate the action

of drugs such as digox.in

Hyperkalemic, hepatoioxic

High oxalic acid content may precipitate

renal stone formation and other renal

disorders

Oxalate nephropathy

Plants have diuretic propertyl i:nd rnay

increase the renal elimination of other drugs

lar et al (2010)

LLryckx anr.t Narcl,.er

i20OS), Marke:ll i20'l 0)

!ifeenkarnp and

Ster,vali (2005)

Wolf Hall (2010)

lsbruckef ar rrl Brir

dock (2006), |<.ataya

e1 eL i201 1 |

Saxena anci Panbo

lia {2003), Stadlbaror

e1. al, (200li), Jha

i2D t0)

Rrhl and MerTers

(2001 )

C )en et a . (11001 ),

\,\(r er al {2011)

Dearing el al. (i1001),

Wojcilrowsl<i et al

(2009)

LE, level of evidence1 Some of these herbs exert their diuretic effects via extra+enal mechanisms with no direct effects on the kictneys (see De.::tng et al . 200 ! )

Izz.o et al. (19!)7) demonstrated that anthranoids could beharmful to the gut epithelium by inhibiting Na+/K+ AIPase andincreasing the activity of nitric oxide synthase. This significantlyincreased intestinal transit due to the alteration in the intestinalwater and salt absorption and the subsequent fluid accumulation.In a study conducted by Nfundal, and l\lunday (1999), a garlic-derived compound was shown to increase the tissue activities of

quinone reductar;e and glutathione transferase in the gastr:oin-testinal tract of the rat. In view of their roles in metabolism, bothenzymes are considered chernoprotective especially from chemicalcarcinogens. In addition to CYP and P-gp mediated mechanisms,the well-known gins,eng-incluced pharmacokinetic HDI may also

be due to its gastrointelstinaI effects especially its inhibitory elfectson gastric secretion (Sr Lz LLlii et a) , 1 9 9 1 ). The potential of rheirr and

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research April 2012 l Volume 3 | Article 69 | 8

Herb-drug interactions

.Bo

os)

cocCOOO

ruNNO-eO

=hoc-N!:Go3PF*.f-,oh or:#q.-04-:'i-o gi-i< E ),Y o= :- ". o .Yq sxA r

Da

6Uo^+N iO .1.

oHEf ==rfo-=j^P 6 oX a 5-.^o- Hi ooX N-tv(o A V:rcii-fi=5c x:x

>v>S

qat) IZJ

6 o ! 999aiancc3 r o e Luo h .z a 6PE 5, 6 .E .eX=ox'cc-;ios=E -, ; E fI;X E P € € :P.Y,=o;i

3 sEE S I iE

o.cs+3'FVf

o-:a-=-r-c=ooo7-=x o-.:o--n.ePE

=€EH€?,=d&d

ooiEe: EvPEE'EF

hooFX>o=

= p' E.,O 6.EEEE E t5o .e'i0t

E 8-.;3* 6PXE€ EEgEE gf;E:S AH,E€! ,EEiE

5LY'o.^N

-YOg F€Eo;':oo.9. F 6'^E > E P)

-E99.Yo6.od rqC'=:oegl.-a.=R 9 :E:qEE€.E' Fa E-!i!PE€ g

=;=-;g€

g 6 F,g88, e.gii

e Et IEE:': E 5r Jg'-sg* c fEE EEisH€ X SEi E.--PEHs P Ec*6 EEE€€

o.cc

,c

E

o=oocao

.cEoal

coX!ooao?

cc-9=.s F .ti6=

o=y

ACs€Ep,^-oijR -69 '>

i PF.Rl: 96-eEcF=E;:92_--o9E

-E P H+FHE E E!54

q)

.c

o!o.

.9.

cio.=_vcY.=7ycx.uJox

a-E -.EF::Q E-6 q .C,).j

GLN.=

o a6i .'6= '=hS x'droI :i** E,'.$.9I EX.X s-.ER3E fr83 f AiJ C

oEF 3 ^si S E S*€ *^SeSlS ifrtEsHc q Y o *x c& #5\555

-a

3l

--tdl.e9:xat^iEdX:E.e9::ooi di

to

C

trTCa

co'-o,.8

q.FC)

Ec

._c

c

cn' .o

>6>F.Y Xo-! coq h

5!vu o!voo>ECD

c.=xEOiE

€3

q:

s!q'b

E .EBgio-^d .: px'9:).;OH i * iF SFc:HXc: F S H> 8\ F * in; .Q.= Y ; S> oS E ,S Eq -ES E r' 8;' $

Aptil2012 |Volume 3 |Article 69 IIwww,fiontiersin.org

IEe0tE

sE= eEE.E8tH9rb6e.E

oo(!oEotr(EEe,E

ocoG.9ttc

o>n:oLtlog,I! ED

E.E

E!CIGtroEoE

Fasinu et al.

,tiCD

?toEo

6'

og!trGoEaatoe6llo

oo;5lloogtg0,

:E

t!

t,0(!

G

EoottEoxoo,o

ah

aooItF

Fasinu et al Herb-drug int{rractions

EFi €€s € $ jfH :, e.p ;r s e Tl€ 3 F 6 .:ijeai F gg oEji gE€,+p !,F$EerEtr€ ; F qE jiH'$€H'fii E = EF ;i ; s F#eg $;g_==EgE;g=3i E : =.9 El f; $ :!-siE EEF€f E3$EEE i E 5E fJ H, 3 iEEF =EJH

t F : g E:s q b E

€ €. ri f; €' E$E-' -g * u: F 2E.s qE Eg E u: J;t*3=l P =: i ?Ef aE ErrE 5h :E€t*5prE=Fg € E€E PE EEg: gE E-fl;;i €gE€sE=B3 i* !;:e €= rB*lrs&E:i -=-EE +3 EF

a;

g n6 E i F € t; s E=t=g $n; f; € g E q grug fr€pgEs ECE €e gg ssn€ fr €:ii n:f lug H,=

s sE gt sEng l iIci sgsF;s sg

@c)@t)o '-c

i!1 coosi,FEo)+^o.c :r- 6A oo, r2.= o o --.,.rg,ai9o J.l o ar'i OC.YO;z@Cy:1=oc.9Y

I 9. Q9F; : o.!: >:tP. e IA' i: i:;Eg < I

;.ck,^-u;.4iEi.i :6io P= 5 FrE Eq,3,8 ; aEG

-ePP 9 ui -n ,4 P*- e

:AgE P €E€E E

6EFF + *i*F F

?E.eo€39,6cs 5 ; " g F ; 6,i E oFt ssasttt+E FfEt E et $ $e Fa E E i i €t$s t^ N': $ [? $E S E * Fn Sg $R ft E'-Y Nd i S i; & SE&E

oIooot

u.lJ

I€r,E.E.E38H3386€.E

c,>9.o;i6.:rTlog)6E''E,E

G

o

oE

6

co

G

oE

o

6

tr

()

o

(oo

,6F

Ap(|| 2012 l Volume 3 | Article 09 | 10Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research

Herb-drug interactions

.6-

o

8<

April 2012 | Volume 3 I Article 69 | 11wwwfrontiersin,org

oooc)

O

-N

b):Nb--=

ooQO - 't:

J=.N=

ONOR^i00oro-OOC* o '6.'=-u)Lr(,

o€.ON-}tr-o oN:JN !fcs +oG;€OO5":"()-N:oiio= NV-=

=trc:AC.:>q;icitoa-+-

Co@9@x

fI-c

aO)l

Eo

.N

!ootrEo:

EO}\o.e;<A{!: ; E : d .Y @'.XE #. c HE, H HH,g EEs €eH=sij "f s iq9A qEq .yF,E€s.q3. I V3€o It.: 6o€6lIb- .: XlqS 3E= ErEE$EE Z EEg

9>o'oto6.>6

bb0b_6rc=!XL 'E 'E *'Etrcc.lgC:ooIG

-9P- E :o,!2 o 9€--E,"io *aE= +l:iJ'-}.-Ftlo>o'>F::g :E q_6€F €gFE.E ; .E:E€ € 9TE; F;935€ EH€

H'EE E EE,lfF =65F8

iE'=XFEe" r- E?Z* E.g€tg 1S+"

@'

=xc3-!-QCLX=RY

Xfr'E;cEg:;.ts)x-:^L -' {.1; ag g'E 6")looF.i Y.l!4Elc;;\896ee.E

J C A 1 dE

@o

oo J! a ?'=.t!q!t=fiotq+n)f;i;dOi:€t*0# 6 = E o)

!D *.-.: o E > aj cxr:Irca:!t,L-car'tBbFE V 9 oo o b fi;iEg;. i 5 €F E E Ef;EE;'= F b ..eF E .V f-EE:EE I n E F -e' ! |.c gh x hi t P, 3# a F 3aE<t36

,^a

.voaoRA

i>gtLIJ O-

a'F6xoo

YC=

!.cfi+UO=P06f,ULLG

.=c 'FpiPPocEPiictE':aocoN

x=a9;o ; H = hr6fDi:5F9c d {: H to o -<l tn< Ac v O (9

6a^

U)

XG

^LCl{ i\E5'6()

U='6 _r! .q

FsH"il#.i+\sFes"$EE{€s 6 s.Fs 6{oq=qq

€Eig sstuE* $ H€Fae$ s=F * sc ge$ B

SE$ e:F s Sg $€s E

.=

.T

ooooI

aoEog0)

Cooo6!d-

Fasinu et al.

Herb--drug interactions

-r-Or)(jTNNN

8683m-3ER ro

-s) R - H ;=ES+q-q38g z ,€ 3 FEd=iSFFHE I n 2 EI:t;-P+;; ; Ea9 2336:''[Ft5==5:9o6oiI€o'rE 5 gBc Slree ESF"q

-@osoooxou@N-<- F72

Pii

oc-o.:G(tl

@@!)q@aaaooooo)c')oo= = o R-J.aa J:===!EOX',TTOD!!E!! fE'_i:fjin-lnnJiIisoo@.yco.y.900ooo3 3 ? P -E3Pe'833R3A E E P E dEgABBAB,Y.Y-.=6.__,_oaz(J O U O <OOO(J(.)OO(J

@6,^-'?E.6PGo,n-g

oi'R950)P?ry3aoo

ra,9.e q

=H bo .E=o o

=>::-.tr6 '

F .X bSUPE AE P M P *dE_EP ETE g F F ;EPFg€:gEE E E € FHE*E*fiEEO

o'->,99PfieP-?.o 9:[j I .9 g.o !)PchXtOYcdr^Lcri-=o yE: o ^9 .>e,99H.#x Y=;i o >.e >l* * E.s2 6>.9E>53 €g€ <r {8 d533€<o

oceco@\9on

.:-..:.=cox Y = lgE-Fv.,9i9E+ E : s =fiE'*giEEEY 6 X 6 F iJ;;i o c d: FF 3 H 9. 9!l>66-PEEd d o a' 90t-id(;e9

.c

OP

>vOLY

:oonro-i-1 4 F FXYOF@=Y]: E @1684 d O

-6

5 xe E- Esfr ER= :F E+H EilE H;, "'-EP -$gEr$ Ee.**e* i *SiFis st'E:lfit=;€ F

EOQoQ)

. E ri 5* F F3 R-*;iN:

*u.ngFE fS;iftS6Fx tr;+F c o o ix

FE5-88$ H8

5v.alc

=ohx.!;=_q

^")=-L.*.EP E *o:{=2--4<;< o 2

oa=oLd

:q^\9 A ,, :

o-o-=t=-ec ,2EE se; f;o o;lt !la2!o(^

a

eEo0)q

Io*5sv.s

!!s

v

Aptil2012lVolume 3lArticle 69 | 12ResearchFrontiers in Pharmacology I Pharmaceutical Medicine and

o,otrEtl,oE

IIJ

firi?oEE.Eq8E9c6

tr

o(!

EoEGEoE

otr

6gtttr

o>t4E,Crtlo9G E'E ._tr

o

GcottoE

Fasinu et al.

o

o(D

ollt::

Fasinu et al Herb-drug interactions

danthron to increase the absorption of fi.rrosennicle, a p,oorlywater-solutrle drug, has been dernonstraterl throuLgh in vitro studies(l,aitlnen et al., 2007). In a study carlied out on rnice, a Chi-nese herbal pIant, Polygonum paleaceunx, sho,rved the potential todeprr:ss the motility of the gastrointestinal tract, inhibit defeca-tion reflex and delay gastric emptying (Zhang. 20011). A similarstudy'demonstrated the inhibitory efFects r:f tvro Chinese tradi-tional lrerbal prescriptions, Fructus aurantii ir,qmatut'us and Radixpaeoniae alba on gastrointestinal rnovernent (irang et aL., 2009).

The absorption of drugs such as phenoxyrnethylperricillin, met-formin, glibenclamide, and lovastatin may b'e reduced by high-fiber herbal products through the sequestration of bile acids(Colalto, 2010). MochiLti ct ai. (2010) reported the ability ofKampc,, a traditional faparrese medicine, to, sl.imulate elevatedintestirral blood flow, and to induce iricreasr:d secre,tion of gas-

trointestinal hormones including motilin,'rrasoactiue intestinalpeptide, and calcitonin gene-related peptide. Similarly anothertradilional fapanese medicine has br:en shown to increase theintestirral secretion of ghrelin, a hunger-relateil hormone, Iead-ing 1:o delayed gastric emptying (lbkita ct i.rl,, r1007; I(alvir-hal;t et a1.,2009; Flattori,20l0; llatr;umura ct a]..20I0). Also,

Qi et rl. (2007) demonstrated the capabiJity of Da-Cheng-Qi-Tang, a traditional Chinese herbal formula, to increase plasmamotillirr, enhance gastrointestinal motility, irnprove gastric dys-rhythLnria, and reduce gastroparesis after abdorninal surgery. Theseeffecl:s have the potential of reducing the intestinal transit timeof concurrently administered drug, vdth t.be risk of reducedabsolption.

Alter,attion in renal elininationThis irvolves herbal products capable of interacting with renalfunctio,ns, leading to altered renal eliminatior.r of drugs. Such inter-actio:n can result from the inhibition o'f tubullr siecreltion, tubularreabsolption, or interference with glornenrlirr filtration (lsnaldet aL,, 2004). In addition to this group o1'herbal products arethose pr16ds61s consumed as diuretics. The mechanir;m of herbaldiuresis is complex and non-uniform. Certai.n herbs increase theglomerular filtration rate but do not stinLulzLte electrolyte secretion

REFEREIUCESAbii, 1'. t\., and Onuoha, E. N. (2011).

Th': chemical constituents of tbeleat: of Aspilia africana as a sci-

entific backing to its tradomeclicalpotentials. Agrlc.,L 6, 28-30.

Agra, M. E, De Freitas, P F., and

Barbosa-Filho, l. M. (2007). Synop-

sis o1' the plants known as nedi-cinal and poisonous in NortheastBrazil. Rev. Bras. Fatmacogn. 17,

114t-t 40.

Agrosi, .M., Mischatti, S., Harrasser,

P. C., and Savio, D (2000). Oralbioavailability of active principlesfto:m herbal products in humans:a stu,jy on Hypericum perforatumextracts using the soft gelatin r:ap-

sul: technology. Plrytomedicine 7,

45ti-t162.

Ajuyr, A. A., Newaz, M., Ilercule, H.,Sal,:h,, M., Bode, C. O., and Oyekan,

A. O (2003). Endothelinlikear:tion of Pausinystalia yohimbeaqueous extract orL vascular andrenal regi,cnal hemodynamrcs rnS;rrague Datvley ruts. Methods

Fitil. Erp CIin Pharnncol 25,

8t7.-822-.

Al-Ali, M., Wahbi, S., Twaij, H., and Al-Badr, A. (.100:t). Tribulus tcrrcstrisipreliminary str:dy of its diuretic and

contractjle effecls atrd comparisonwrth Zea nays l. Ethtropharmacol.

8!i,257-:,7.60.

Albert, A., Altabre, C., B;116, F., Buendia,

E,, Cabero, A., Cancelo, M. J.,

Castelo-Branco, C.., Chantre, P,Duran, M., Ilaya, J., Imbert, P.,

JuLliir, D,, l,anchares, J. L., Llaneza,P., Manutrens;, M., Minano, A.,

Qui:reda, F., Ribes, Ci., and Vdzquez,

F. (2002). Efficacy and safety of a

p\toestrolgen prepirration derired

while some others act as direct tubular irritants (Closbr. et al., 200 L;

Al-Ali e t al., 200.1). Some herbs capable of interacting with renalfunctions and drug elimination are presented in Table 5.

Ph armacodyna m i c syne ryy, a dd iti on, a nd a ntago n ism

Herb-drug interaction can occur through the synergistic or addi-tive actions of herbal products with conventional medications as

a result of affinities for common receptor sites (N,Ia ct al., 2009).This can precipitate pharmacodynamic toxicity or antagonisticeffects (Table 6). Like most other herbs, SI{ contains complexmixture of phltochemicals including phenylpropanes, naphtho-danthrones, acylphloroglucinois, flavonoids, flavanol glycosides,

ancl biflavones. Hyperforin is known to inhibit the reuptake ofneurotransrritters (dopamine, serotonin, noradrenalin) and isbelieved to be the bioactive responsible for the antidepressantactivity of SfW.

GONCLUSION

Concomitant use of herbs and conventional drugs may presentwith untorvard events. Evidence available in literature indicatesvarious mechanisms through which this can occur. By interactingwith conventional rnedication, herbal remedies may pr:ecipitate

manifestations of toxicity or in the other extreme, therapeuticfailure. A good knowledge of the potential of contnonly con-sumed herbal medicines to interact with prescription medicines,ilrespective of the nature of evidence available, will equip healthprofessionais in their practice. Apart from those demonstrated insignificant number of human subjects, not all reported HDIs are

clinically significant. As such, more clinicall). relevant research inthis area is necessary. This review provides information on com-monly used herbs and their potentials for HDI within the levels ofevidence currently available.

ACKNIOWTEDGMENTSThe authors rvill iike to acknowledge the support of HOPEKapstadt-Stiftung (HOPE Cape ltown) and the StellenboschUniversity Rur:al Medical Education Partnership Initiative(SURMEPI) for providing ftinds lbr: this study.

fton Glycine mm (L.) Merr in cli- ABC transporters (P-glycoprotein,

macteric symptomatology: a multi- MRP2, BCRP) by flavonoids andcentric, open, prospective and non- drug response. I. Pharm. Sci. 99,randomized Irial. Phytomedicine 9, 598-617.85-92. Amacher, D. E. (2010). The effects

Al-Deeb,I.D.,Arafat,T.A,,andIrshaid, of qtochrome P450 induction byY M. (2010). The effect of Licorice xenobiotics on endobiotic metab-drink on the systemic exposure of olisrn in pre-clinical safety stud-Verapamil in rabbits. Drug Metab. ies. Toxicol. Mech Methods 20,Lett. 4,173-179. 159-166.

Al-Flabori, M. (2005). The potential Almaniri, D,, Fiore, C., Mattarello, M.adverse effects of habitual use of J., Bielenberg, J., and llalermo, M.Catha edulis (ldtat). Expert Opin. (2002) History of the endocrineDrug Saf. 4, I 145-1 I 54. effects of Licorice. E:rp. Clin.

Alkharfr, K. M., and Frye, R F. (2007). Endocrinol. Diabetes 110,257-261,.

Effect of valerian, valerian/hops Arteaga,I.,Aldrade-Cetto,A.,andC6r-extncts, and valerenic acid on glu- denas, R. (2005). Larrea triden-curonidation it vitto. Xenobiotica teta (Creosole bush), an abundant37,113-123. plant of Mexican and US-American

Alvarez, A. I., Real, R., Perez, M., Men- deserts and its metabolite nordihy-doza, G., Prieto, J. G., and Merino, G. droguaiaretic acid, l, Ethnopharnn-(2010).Modulationoftheactivityof col 98,23I-239.

www.frontiersin.org Aptil 2012 | Volume 3 | Article 69 | 13

Fasinu et al HerFdrug interactions

Asdaq, S. M., and Inamdar, M. N.(2010). Pharmacodynamic inter-action of captopril with garlicin isoproterenol-induced myocar-dial damage in rat . Phytother. Res.24,

720-725.Asdaq, S. M., md Inamdar, M. N.

(2011). Pharmacodlmamic andpharmacokinetic interactions ofpropranolol wilh garlic (Alliumsativum) in ruts. Etid. Based

Complement, Alternat. Med. 2011,

824042,

Asdaq, S. M., Inamdar, M. N., and Asad,

M. (2009). Effect of conventionalantihypertensive drugs on hypolipi-demic action of ga rlic ln rats. LdianI. Exp. BioL +7,176-181.

Ashihara, H., and Crozier, A. (2001).

Caffeine: a well-known but littlementioned compound in plant sci-

ence. Trends Plsnt Sci. 6,407-4I3.Aungst, B. J. (2000). Intestinal perme-

ation enhancers. J. Pharm. Sci. 89,429-442.

Ayuba, V. O., and Ofojekwu, P C.

(2005). "Effects of extracts of driedseeds ol Lofoache, Datura innoxia as

anaesthesia on the African catfish

Clarias gariepinus 6ngerlings," in19th Anrunl Conference of the Fish-

et ies Society of Nigeria. Available at:

http://aquaticcommons.org/3986/

1/25.pdf laccessed November 03,

201 11.

Bafna, A., and Mishra, S. (2010).

Antioxidant and immunomodula-tory activity of the alkaloidal frac-

tion of Cissampelos pareira linn. Sci.

Pharm,78,2I-3I.Balderas, J. L., Reza, V, Ugalde, M.,

Guzm6n, L., Serrano, M, I., Aguilar,A., and Navarrete, A. (2008). Phar-

macodynanric interaction of the

sedative effecrs of Ternslroemia

pringlei (Rose) Standl. with six cen-

tral nervous system depressant drugs

in mice. J. Ethnopharmacol. II9,47-52.

Baquer, N. 2., Kumar, P, Taha, A., Kale,

R. K., Cowsik, S. M., and Mclean,P. (2011). Metabolic and molec-ular action of Trigonella foenum-graecum (ferngreek) and trace met-als in experimental diabetic tissues.

J, Biosci.36,383-396.Barbenel, D. M., Yusufi, 8., O'Shea,

D., and Bench, C. J. (2000). Maniain a patient receiving testosterone

replacement postorchidectomy tak-ing St lohns wort and sertraline. IP sychopharmacol. 14, 84-86.

Barnes, J., Anderson, L. A., Gibbons, S.,

and Phillipson, J. D. (2005). Echi-nacea species (Echinacea angustifo-

lia (DC.) Hell, Echinacea pallitla(Nutt.) Nutt,, Echinacea purpufea(L.) Moench: a review of their

chemistry, pharnacology and clin-ical properties. /, Pharm, Pharmacol,(? oto-os[

Bebawy, M., and Sze, D. M. (2008). Tar-

geting P-glycoproteil for effective

oral anti-cancer chemotherapeutics.

Curr. Cancer Drug Thrgets 8,47-52.Bensoussan, A., Myers, S P., Wu, S M,

O'Connor, K. (2004). Naturopathicand Western herbal medicine prac-

tice inAustralia - a worKorce survey.

Complement. Ther. Med, 12,17-27.Berginc, K., and Kristl, A. (2012). The

effect ofgarlic supplements and pby-tochemicals on the ADMET prop-erties of drugs. Expert Opin. DrugMetab. Toxico l. 8, 295-310.

Bihl, G., and Meyers, A. (2001). Recur-

rent renal stone disease - advances

in pathogenesis and clinical manage-

ment Lancet 358, 65 1-656.

Bilgi, N., Bell, K., Ananthakishnan, A.N., and Atallah, E. (2010). Imatiniband Panax ginseng: a potential inter-action resulting in livertoxicity. Anr.Phar m acother, 44, 92G928,

Birmes, P,, Coppin, D., Schmitt, L., and

Lauque, D. (2003). Serotonin syn-

drome: a brief review. CMA] 168,

r439-1442.Bodeker, G. (2007). Traditional health

systems: policy, biodiversity, and

global interdependence. l. AbernComple m en t. Me d. l, 23 l-243

Bonetto, N., Santelli, L., Battistin, L., andCagnin, A. (2007). Serotonin syn-

drome and rhabdomyolysis inducedby concomitant use of triptans, flu-oxetine and bypericutt. Cephalalgia

27, 1421-1423.Borrel, M. N., Pereira, E., Fiallo, M.,

and Garnier-Suillerot, A. (1994).

Mobile ionophores are a novelclass of P-glycoprotein inhibitors.The effects of ionophores on 4'-O-tetrahyd ropyranyl- adriamycinincorporation in K562 drug-resistant cells. Eur, J. Biochem,223,125-t33.

BorrelJi, F., Capasso, R., and lzzo, A. A.(2007). Garlic (Alliun satitum L.):adverse effects and drug interactionsin humans. Mol. Nutr. Food Res.5I,1386-1397.

Borrelli, F., and Izzo, A. A. (2009). Herb-

drug interactions with St lohn's wort(Hypericum perforafaz): an updateon clinical observations. r4,4PS/. 11,

7 10-727 .

Bosch, T. M. (2008). Pharmacoge-

nomics of drug-metabolizingenzymes and drug transpol:ters rn

chemotherapy. Methods MoL BioL

448,63-76.Boucher, B.1., and Mannan, N. (2002).

Metabolic effects of the consump-tion of Areca catechu. Addict. BioI.7,103-1 10.

Boullata, j. L, and Nace, A. M. (2000).

Safety issues with helbal medicine.P h ar m a c o th e r ap y ?-0, t\. 57 -2 6c).

Bray, B. J., Perry, N. B,, Menkes, D.

B., and Rosengren, ll. J. (2002,). St

fohns wort extract induces CYP3Aand CYP2EI in the liwiss Vt/ebster

motse Toxicol Sci. 66, 27 -33Brown, L., Heyneke, O, Brown, D.,

van Wyk, J. P, and llamman, J. H.(2008). Impact of tra<litional medi-cinal plant eKtractr; on antiretroviraldrug absorption. /. Etlu ophannacol.

1 19, 588-s92,Calixto, I. B. (2000). Efficacy, safety,

quality control, markr:ting and reg-

ulatory guidelines for herbal med-icines (phytotherapeutic agents).Bnz. I. Med. Biol.. Res.33,179-189

Capasso, F., Gaginella, T. ll., Grandolini,G., and Izzo, A. A. (20(13) Phytother-apy: A Quick Relbrence to Herbal

Medicine. Berlin: Spriger-Verlag.

Cassidy, A. (2003). Are herbal remedies

and dietary supplements safe and

effective fbr breast cancer patients?

Breast Cancer Res, 5, 300- 302,

Chan, T Y. (2001). Interaction between

warfarin anrl clanshen (Sahtia mil-tiorrhiza). lVrr. Phar macothet 35,50I-504

Chao, M, T, Wade, C., arrd Kronen-berg, F. (2008). DiscloslLre ot com-plementary and alterniltive medicineto conventional meclical providers:

variation by race/ethnicity and typeof CAM. l, NatL Med, Assoc. 100,

1341-1349.Chen, C. L., Fang, l{. C., Chou, K.

I., Wang, I. S., and Chung, H. M.(2001). Acute oxalate nephropathyafter ingestion of star fruit. Am. /.Kidney Dk. :\7, 478-+it2.

Cheng, B., Hung, C. T., ancl ClLitL, W.(2002). Hertral medicine and anaes-

thesia. Horrg Kong Med l. B, I23-I30.Chitturi, S., anrl larrell, G, C. (2000).

Herbal hepatotoxi<ity: an expandingbut poorly defined problem /. Gas-

troenterol H epotol. 15, 1 093-1099.Chitturi, S., and Farrell, c. C. (2008).

Hepatotoxic slimmirrg aids andother herbal hepatotoxins. jr, Gas-

tro enterol Hepilol 2 3, 366-37 3.

Choi, l. S., and Burm, I. P (2006).

Enhanced nirnodipine trioavailabil-ity after oral arlministratiorr ofnimodipine with morin, a flavonoid,in rabbits. Arch Phlrm. Res. 29,

333-338.

Circosta, C., Pasquale, R. D., Palurnbo,

D. R., Sanperi, S,, and Occhi-uto, F. (2006). Er;troge:nic activityof standardized exlra':t of Angelica

sinensis. Phy tothet. Res. 2Q, 665- 669.

Clement, Y N., Williams, A, F,, Khan,K., Bernard, T., Bhola, S., Fortun6,M., Medupe, O., Nagee, K., and

Seaforth, C. E. (2005). A gap between

acceptmce and knowledge of herbal

remedies by physicians: the need

for educational intervention. BMCComplement. Altern. Med. 5, 20.cloi: I0. 1 I 86/I472- 6882- 5 -20

Colalto, C. (2010). Herbal intr:ractionson absorption ofdrugs: mechanrsms

of action and clinical risk asscss-

menl Pharmacol. Res.62,207 -227-Coppola, M., and Mondola, R. (2012).

Potential action of betel rrlkaloids

on positive and negative symptomsof schizophrenia: a review. N'ord. J.

Psychiatry 66,73-78.Cordia, W., and Steenkamp, V, (2011).

Drug interactions in African .herbal

remedies. D rug Metabol. Drug Inter-act. 26, 53-63.

Cox, M. C., Low, I., Lee, |., Walshe, f.,Denduluri, N., Berman, A., Perme-

nteq M. G., Petros, W. P, .Price, D.

K., Figg,W. D., Sparreboom,y'r., andSwain, S. M. (2006).Influenr:e of gar-

hc (Allium satitum) on the pharma-cokinetics of docetuel. Clin. ()ancer

Iles. 12,4636-4640.Crijns, A. P,, se Snet, P. A., van

den Heuvel, M., Schot, B. \4i, andHaagsma, E. B. (2002). Acutehepati-tis after use of a herbal preparationwith greater celan dine (Chel.id cnwnmajus). Ned. Tijdschr. Geneedcd. 19,

r2q-128.Crosby, E. C., Dolan, R. L., Br:nson,

J. E., Luetkemeier, M. J., Barton,R. G., and Askew, E. W. (2001).

Ilerbal diuretic induced dehydrationand resting metab olic rate. Mr:d. Sci.

Sports Exetc.33, 5163.

Cullen, I. M. (2005). Mechanir;tic clas-

sification of liver injury. Tbxicol,

PathoL33,6-8.Dannawi, M. (2002). Possible serotonin

syndrome after combinatiorr o,f bus-pirone and St John's wort. )'. Psy-

choph ar m a c ol. (Oxford) 16, 401.

Dasgupta, A., Kidd. L., PoindexLer, B.

J., Bick, R. I. (2010). Interfere:nce ofhawthorn on serum digoxin mea-

surements by immunoassay; andpharmacodynamic interactiorr withdigoxin, Arch. Pathol Lab. IvIed.134,I 188-1 192.

De Almeida, E. R., Melo, A. M., and

Xavier, H. (2000). Toxicolog:ical eval-

uation of the hydro-a.lcohol extractof the dry leaves of Peumts boldus

and boldine in rats- Phytother. Res.

14,99-102,De Berardinis, V, Moulis, C., Mau-

rice, M., Beaune, P., PessiLyre, D.,Pompon, D., ancl Loeper', l. (2000).

Human microsomal epoxide hydro-lase is the target of germzLnder-

induced autoantibodies on the sur-face of human hepatocytes. Mol.Ph armacol. 3, 542-551,.

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research April 2012 | Volume 3 I Article 69 | 14

Fasinu el al Herb-drug interactions

De Vlaat, M. M., Hoetelmans, R.

M. Vl, Mathdt, R. A,, van Gorp,E. C,, Meenhorst, P. L., Mulder,

I. r/y'., and Beijnen, l. H. (2001).

Drug interactions between St lohn'swoft and nevirapine. AIDS 15,

42Ct-421.

DearirLg, D. M., Mangione, A. M., andKarasov, W H. (2001). Plant sec-

ondary compounds as diuretics: an

overk)oked consequence Am. ZooI.

41,890-901.

D6ciga-Clampos, M., Rivero-Cruz, I.,Arrialla-Alba, M., Castafl eda-Corral,G., Angeles-L6pez, G. E., Navar-rete,1\., and Mata, R. (2007). Acutetoxicity and mutagenic activity ofMexican plants used in traditionalme,Cicine. l. Ethnopharmacol- 1t0,334-342.

Degorter, M. K., Xia, C. Q., Yang, l. J.,

ancl K.im, R. B. (2012). Drug trans-porter:s in drug ef6.cacy and toxicity.Arnru. Rev. Pharmacol. Toxicol. 52,249-273.

Delevr:, L. D., Schulman, H. M, andMacD,onald, G. B. (2002). Toxicinjury to hepatic sinusoids: sinu-soidal obstruction syndrome (veno-

occlur;ive disease). Senin Liver Dis.)) )7-L1

DelgocLa, R., and Westlake, A. C. G.

(2004). Herbal interactions involv-ing r:ytochrome P450 enzymes:

a rniiri review Toxicol Rev. 23,

239-249.Di,Y N'L, Li, C. G., Xue, C. C., and Zhou,

S. t (2008). Clinical drugs that rnter-act with St. John's wort and impli-cation in drug development. Clrr.Pharn. Des. 14, 1,7 23-17 42.

Dresser, (i. K., Schwarz, U. I.,Wilkinson,G.Il., andKim,R. B. (2007). Coordinatr: i:nduction of both c).tochromeP4503A and MDRl by St John's wortin healthysubjects. Clin. Pharmacol.

Ther.13,4L-50..Dnraz<t,T, A., Lassman, C., Han, S. H.,

Saalb, S., Lee, N. P, Kawano, M.,Sag;gi, B., Gordon, S., Farmer, D. G.,

Yersiz, H., Goldstein, R, L., Ghobrial,M., arrd Busuttil, R. W. (2004). Ful-mirrarrtliver failure due to usnic acid

for weight loss. Am. I. Gastroenterol.

5,950-952.Eichhorn, T., and Efferth, T. (2011).

Pglycoprotein and its ilhibitron rntunrors by phytochemicals derivedfrorn Chinese herbal medicine /.Ethnopharmacol PMID: 2i859398.

IEpub ahead ofprint].Emilio, L., Ghisalberti, E. L., Pennac-

chio, 1t4,, and Alexander, E. (1998).

Surrey of secondary plant metabo-lites,rith cardiovascular activity.Pharn. Biol. 36, 237 -279.

llmma, C. (2008). Lycopoditm simili-aplex-i\d\ced acute hepatitis: a case

rcpoft, Eut, J. ()asn oenterol. Hepatol.

20,46947t.Engelberg, D., McCutr:heon, A., and

\A/iseman, S. (2001). A case ofginseng-inrJuced mania. J. CIin. Psy-

cho phar macol. 2I, 535-537 .

Ernsl:, E. (2002). St John's wort sup-pJements endanger the success oforg:rn traxrsplantali<tn. Arch. Surg,

137,316-319.Ernsl, E. (200,4). Are her-bal rnedicines

elfective? ,fnt. J. CIin. Pharmqcol.

Ther. 42, IliT-159.Ernst, ll. (2001t). 'fhe efficacy of herbal

medicine - an ovewiew. Fundan.CIir. Plnrrnacol 19, 405409,

Fabricart, D. Ii., and Farnsworth, N. R.

(2001). The value o1'plants used intraditional medicine for drug dis-ccvery. Ent iron. Heillth Perspect. L09,69-75.

Fakeye, T. O., and Onyenadu, O. (2008).

Evaluation of knowledge base ofhospital pharnacists and physi-cians on herbal mecUcines in South-western Nigeria. Plnrm. Prart.6,88-92.

Fang, Y S, Shan, D. M., Liu, I. W,Xr, W, Li., C. L, Wu, H. 2., and

Ji, G (2009). Effect of constituentsfronr ftuctus Aurantii immaluwandrcdixFaeoniae aJba on gastroin-testinal movenrent. Planta Med. 7 5,

24-3r.Farkas, D., Shader, R. 1., von Moltke,

L. L., and Greenblatt, D. J. (2010)."l4echanisrns and consequences ofdrul;-drug interactionsl' in Pharma-ceutical Sciences Encyclopedia: DrugDiscovery,, l)evelopment, and Manu-

facturing ()ohn Wiley & Sons, Inc.).doi: 10. r00;2/9780 47 (t57 1224.pse055

Fasinu, P., Bouic, P- /., and Rosenkranz,

B. (:1012). Liver-based in vitro tech-nologies for drug biolransformationstrrrlies - a r eview Curr. Drug Metab.

13,,II5-22t1.Feltens{:ein, M.. W., Lambdin, L. C.,

Givrzera, Il., Ranjith, H., Dhar-malatne, !V., Nanalakkara, N. P.,

Khan, I. A., and Sufl<a, K. J.

(2003). Arxioll.tic properties ofpiper methysticum extract samples

and fractions in the chick social-separation-strcss procedrre. Phy-

to ther. Re s. 17, 210-216.J:'erguson, C. S., and 'Iyndale, R, F.

(2011). Cyochrome P450 enzymes

in the brai:r: emerging evidence ofbi,rlogical significance. Trends Phar-rn,qcol. Sci. :\2, 7 O8.-7 14.

lierrara, L., .Montesano, D., and Sena-

tore, A. (2001). The distribution ofminerals and flavonoids in the tea

pltnt CatnelLia sinensis. Farmaco 56,397.,40r.

Irugh-Berman, A. (2000). Herb-druginteractions. Loncet 355, I 34-l 38.

Gaillad, Y., and Pepin, G. (2001). Case

report: LC-EI-MS determination ofveratridine and cevadine in two fatalcases of Veratrum album porsoning.

J. An aI. Toxicol. 25, 48 1-485.Galindez, I. 5., Lanza, A. M. D., and

Matellano, L. F. (2002). Biologicallyactive substances from the genus

Scrophularia . Phat m. Biol. 40 , 45-59 .

Gilani, A. H., Khan, A. U., Raoof,

M., Ghalur, M N., Siddiqui, B. S.,

Vohra, W, and Begum, S. (2008).

Gastroinl.esLinal, selective airways

and urinary bladder relaxant effects

of Hyoscyantus niger arc mediatedthrough dual blockade of mus-carinic receptors and Ca2* chan-nels. Fundam. CIin. Pharmacol 22,

87-99.Gilca, M., Gaman, L., Panait, 8., Stoian,

I., and Atanasiu, Y. (20\0). Che-

Iidonium majus - an integrativereview: traditional knowledge ver-

sus modenr frndings Forsch. Kom-plem entmed. 17, 241- 248.

Giveon, S. M., Liberman, N., Klang,S., and Kahan, E. (2004). Are peo-

ple who use 'natural drugs' aware oftheir potentially harmful side effects

and reporting to family physician?

Patient Edu c. Couns. 53, 5-Il.Goh, S.Y, and Loh, K. C. (2001). Gynae-

comastia and the herbal tonic "dongql:ai." Singapore Med. J. 42, D5-116.

Greeson, J. M., Sanford, B, andMonti, D. A. (2001). St. Iohn'swort (Hypericum perforntum\: a

review of the current pharmacolog-ical, toxicological, and clinical lit-erature, Psychopharmacology (BerI. )r53,4024r+.

Gurley, B. J., Gardner, S. F., Hubbard,M. A., Williams, D. K., Gentry, W. 8.,

Cui,Y, andAng, C.Y (2005a) Clin-ical assessment of botanical supple-mentation on cFtochrome P450 phe-notypes in the elderly: St lohn's wort,garlrc otl, Panax ginseng and Ginkgo

biloba. Drugs Aging 22,525-539.Gurley, B. J., Gardner, S. E, Hubbard,

M. A., Williams, D. K., Gentry, W. B.,

Khan, I. A., and Shah, A. (2005b),

In vivo effects of goldenseal, kava

kava, black cohosh, and valerian on

human cytochrom e P450 I A2, 2D6,2EI and 3A415 phenorypes. Clin.Pharmacol, Ther.77 , 415-426.

Hafner, V, Jager, M., lvlatthee, A. K.,

Ding, R., Burhenne, 1., Haefeli, WE., and Mikus, G. (2009). Effect ofsimultaneous induction and inhibi-tion of CYP3A by St lohn's wort andritonavir on CYP3A activity. CIin.

Pharmacol. Ther. 87, 19I-196Hamann, G. L., Campbell, I. D., and

George, C. M. (2011). Warfarin-cranberry juice interaction. Ann.Phqrmqcother. 45, e17 .

Hattori, T, (2010). RiRunshito and

ghrelin. Int. l. Pept. 2010, pii: 283549.

He, L., and Liu, P. (2005), Effectof Lycium barbarum polysaccha-

rides on oxidative stress of dia-betic nephropathy in type 2 dia-betic rats. Chinesel. Hosp. Phann. 12,

34-40,He, S. M., Li, R., Kanwar, l. R.,

and Zhou, S. F. (20r1). Struc-tural and functional properties ofhuman multidrug resistance pro-tein 1 (MRPI/ABCCI). Curr. Med.

Chem, 18,439-481.Henderson, L., Yue, Q. Y., Bergquist,

C., Gerden, 8., and Arlett, P. (2002).St lohn's wort (Hypericuffi perfora-tum): drtg interactions and clinicaloutcomes. Br. J. CIin. Pharmacol.54,349-356.

Hiratsuka, M. (201I). In vitro assess-

ment of the allelic variants ofcytochronre P450. Drttg Metab.

Pharmacokinet. IEpub online ahead

of printl.Hojo,Y., Echizenya,M., Ohkubo,T., and

Shimizu, T. (20 1 1). Drug interactionbetween St fohn's wort and zolpidemin healthy subjects. I Clin. Pharm.

Ther. 36,71r-715.Hokkanen, J., Tolonen, A., Mattila, S.,

and Turpeinen, M. (201I). Metab-olism of hyperforin, the active con-stituent of St. John's wort, in humanIiyer microsomes. Eur. J. Pharm. Sri.

42,273-284.Homsy,I., King, R., Tenywa, |., Kyeyune,

P, Opio,A., Balaba, D. (2004). Defin-ing minimum standards of practicefor incorporating African traditionalrnedicine into HIV/AIDS preven-tion, care, and support: a regionalinitiative in eastern and southernAfrica. J. Altern. Complement. Med.

10,905-910.

Howell, L, Kochhar, K., Sapvell, R. Jr.,

Zollinger, T, Koehler, f., Mmdzuk,C., Sutton, B., Sevilla-Martir, 1., and

Allen, D. (2006). Use ofherbal reme-dies by Hispanic patients: do theyinform their physician? J. Am Board

Fam. Med. 19,56d578.Hoyland, H. K. (2011). Use of Saint

John's wort against mild depres-

sion. Tidsskr. Nor. Laegeforen. 731,

837-839.Hsieh, M. J,,\en,Z. S., Chen, S. C., and

Fang, C. C. (2008). Acute choliner-gic syndrome following ingestion ofcontaminated herb aI extract. Em erg.

Med. J.2s,781-782Hr,Z,,Yng, X., Ho, P. C., Chan, S. Y,

Heng, P W., Chan, E., Duan, W, Koh,H. L., and Zhou, S. (2005). Herb-drug in[eracl.ions: a Iiterature review.

Drugs 65,1239-1282.Eltn6 2' Xiao, B., Wang, X., Li, Y,

and Deng, H, (2003). Betel nut

www.frontiersin,org April 2012 | Volume 3 | Arlicle 69 | 15

Fasinu et al. Herb-drug interatctions

indulgence as a cause of epilepsy.

Seizure 12,406408,Huxtable, R. J., and Cooper, R. A.

(2000). "Pyrrolizidine alkaloids:physicochemical correlates ofmetabolism and toicity:' in Nqturaland Selected Synthetic Toxins, eds A.

T. Tu and W. Gaffreld (Washing-

ton: Anerican Chemical Society),

100-l 17.

Iqbal, M., Sharma, S. D., Okazaki, Y.,

Fujisawa, M., and Okada, S. (2003).

Dietary supplementation of cur-cumin enhances antioxidant andphase II metabolizing enzymes in

ddY male mice: possible role in pro-tection against chemical carcinogen-

esis and toxicity. Pharmscol. Toxicol

92,33-38.Isbrucker, R. A., and Burdock, G A.

(2006). Risk and safety assessment

on the consumption ofLicorice root(Glycyrrhiza sp.), its extract and

powder as a food ingredient, withemphasis on the pharmacology and

todcology of glycyrrhizin, Regul.

Toxi col. Ph ar m acol. 46, 167 -I92.lsnard, B. C., Deray,G., Baumelou, A.,Le

Quintrec, M., andVanherueghem, J.

L. (2004). Herbs and the kidney. An.J. Kidney Dis.44, l-t I.

Iwamoto, M., Kassahun, K,, Tioyer, M.D., Hanley, W D., Lu, P,, Rhoton, A.,

Petry, A. S., Chosh, K., Mangin, Ji,DeNoia, E. P, Wenning, L. 4., Stone,

J. A., Gottesdienet K. M., and Wag-

ner, J. A. (2008). Lack ofa pharmaco-kinetic effect of raltegravir on mida-zolam: in vitro/in vivo correlation. ,L

Clin. Ph ar macol. 48, 209-2\ 4.

Iwanaga, K., Hayashi, M., Hamahata,Y., Miyazaki, M., Shibano, M.,Taniguchi, M., Baba, K., and Kakemi,M. (2010). Furanocoumarin deriv-atives in Kampo extract medicinesinhibit cytochrome P450 3A4 and

P-glycoprotein. Drug Metab. Dispos.

38, 1286-1294.Izzo, A. A. (2005). Herb-drug interac-

tions: an overview ofthe clinical evi-dence. Fundam. CIin, Pharmacol. 19,

l-16.Izzo, A, A., and Ernst, E. (2009).

Interactions between herbal med-icines and prescribed drugs: an

updated systematic review. Dr ugs 69,1777-r798.

lzzo, A. L, Sautebin, L., Rombola, L.,

and Capasso, F. (1997). The roleof constitutive nitric oxide synthase

in senna- and cascara-induced diar-rhoea in the rut. Eur, I, Pharmacol

323,93-97.lha, V (2010). Herbal medicines and

chronic kidney disease, Nephrology(Cailton) 15, 10-17.

Johne, A., Schmider, J., Brockmciller,

J., Stadelmann, A. M., Stormer, E.,

Bauer, S., Scholler, G., Langheinrich,M,, and Roots, L (2002). Decreasedplasma levels of amitriptylile arrd its

metabolites on comedication withan extract from St. John's wort(Hyperiam perforatunt). J. Clin.P sy ch o ph a r m acol. 22, 46-5 4.

Kataya, H H, Hamza, A. A, Ramadan,

G. A., and Khasawnch, M. A. (201 t).Effect oflicorice extract on the com-plications of diabetes nephropathyin rats, Drng Chem. Toxicol. 34,10 1-108.

Katoh, M., Yoshioka, Y, Nakagawa, N.,and Yokoi, T. (2009). Effects offapanese herbal medicine, Kampo,on human UGTlA1 aclivity. DrlgMetab. Phar macokinet. 24, 226-23 4.

Kauf?nan, D., Kdly, J., Rosenberg, L.,

Arderson, T. E., and Mitchell, A./'. (2002). Recent patterns of med-ication use in the ambulatory adultpopulation of the United States.

/4M4287,37-44.Kawahara, H., Mitani, Y, Nomura, M.,

Nose, K., Yoneda, A., Hasegawa,

T, Kubota, A., and Fukuzawa, M.(2009). Impact of rikkunshito, an

herbal medicine, on delayed gas-

tric emptying in profoundly hand-icapped patients. Pediat. Surg. Iflt.25,987-990.

Kennedy, I., Wang, C., and Wu, C

(2008). Patient disclosure aboutherb and supplement use amongadults in the US. Evid. Based Com-

plement. Alternat. Med. 5, 451,456.Kent, U. M., Aviram, M., Rosenblat,

M., and Hollenberg, P F. (2002),

The Licorice root derived isoflavanglabridin inhibits the activities ofhuman cytochrome P450S 3A4,2B6,and 2C9. Drug Metab. Dkpol 30,709-7 15.

Kessler, R. C., Davis, R. B., Foster, D. F.,

Van Rompay, M. I., Walters, E, E.,

Wilkey, S, A., Kaptchuk, T. J., and

Eisenberg, D M. (2001). Long-termtrends in the use of complementaryand altcrnative medical therapies inthe United States. Ann. Intern. Med,

1.35,262-268.

Kim, B. H., Kim, K. P, Lirn, K. S.,

Kim, J. R., Yoon, S. H., Cho, J. Y,Lee, Y O., Lee, K. H., lang, I. J.,

Shin, S. G., and Yu, K. S. (2010a).

Influence of Ginkgo biloba extracton the pharmacodlnamic effects

and pharmacokinetic properties ofticlopidine: an openJabel, random-ized, two-period, tlvo-trearmenr,two-sequence, single-dose cLossover

study in healthy Korean male volun-teers. CIin. T her. 32, 380-390.

Kim, 8., Sy-Cordero, A., Graf, T N.,Brantley, S. 1., Paine, M. F., md Ober-Iies, N. H. (2010b). Isolation and

identification of intestinal CYP3A

inhibitors from cranberry (Vac-

cinium macrocarpon) using humanintestinal microsomes. Planta Med.

77,265-270.Kleiner, H. E.,lja, X., Sorroda, J., Zhang,

L Pontius, li,, Abey, J,, Evans, R. M.,Moore, D. D., arrd DiGiovanni, J.

(2008). Effrrrs ol' naLturally occur-ring coum:Lrins on hepatic drug-metabolizing enzynes in mir:e. Tox-

icol. Appl. P harma col. 232, 337 -350.Klepser, T. 8., Dour:etn:, W l(.. and

Horton, M. R. (2000), Assessment

of patients' perceptions and beliefsregarding herbal th er tples. Pharnn-cotherapy 2(J,83-87 .

Knight, A. P, and lValter, R. G.(2002). "Plants affecting the car-

diovascular system," in A Guide

to Plant Poisoning of Anitnals in

North America, eds A, P. Knightand R. G. Walter Available at:

http://M, ivis. org/special_trooks/Knight/chap2-/ivis.pdl: IaccessedNovember 05 201 tl.

Krishna, R., and Mayer, L, D. (2001).

Modulation of .P-glycoprotein(PGP) rnedialed multidrugresistance (lvlDR) using chemosen-

sitizers: recent irdvances in thedesign of selective [4DR modula-tots. Curr. Med. Chem. AnhcutcerAgents I, I63-f74.

Lai, M. N., Wang, S. M,, Chen, P. C.,

Chen, Y. Y, and V/al1;, l. D. (2010).

Population-based caser-control studyof Chilese tLelbal products contain-ing aristolochic ircid and r.rrinary

tract cancer risk. ,L Na:tl. Cancet Inst.

102,179-186.

Laitinen, L., Thkala, 8., Vuore-ta, H.,Vuorela, P, Kaukonen, A. tr4., and

Marvola, M. (2007). ;\nthranoid lax-ative influence the rlbsorption ofpoorly permeable drrrgs in humanintestinal cell culture model (Caco-

2). Eur. I. Pharrn, 'Biopharm. 66,

13F14s.Lala,L. G.,D'Melto,P. M., andNaik,S. R.

(2004). Pharmacokin,etic and phar-macodynamic studies on interactionof "Trikatu' with diclc,fenac sodium.

l. Ethnoph ar macol 9l, 277 -280.Lange, D. (2000). Consetwtion and

Sustainable use of Adonis Vernalis,

a Medicinal Plant in InternationalTrade. Bonn: Federal Agenq' forNature Conr;ervation, 88.

Larsen, A K., .Escargueil, A. 11., andSkladanowski, A (2000). Resistance

mechanisms associated with altered

intracellular distriburion o1 anti-cancer agents. Phatmacol Ther.85,217-229.

Lau, W. C., Welch, T, D., libields,T., Rubenfire, M, l-antry U. S.,

and Gurbel, P A, (2011). Theeffect of Sr Johnt wort on the

pharmacodynamic responsie ofclopidogrel in hyporr:sp'onsrve

volunteers and patients: increasedplatelet inhibition by enhancementof CYP3A4 netabolic activity.

J. Cardioyasc. Pharnacol- 57,

86-93.Lawere, S., andMahoney, M. C (2005).

St John's wort. Am Fam. Physician

72,2249-22s4.Leclercq, I. A., Farrell, G. C., Field,

J., Bell, D. R., Gonzalez, ll, .1., andRobertson, G. R. (2000). CYP2EIand CYP4A as microsonral cata-

lysts of lipid peroxides in rnurinenonalcoholic steatohepatitis..l Clin.Inyest. I05, 1067-I07 5.

Lee, J Y, Duke, R K., Trau, V H.,l{ook, f. M., and Duke, C. C. (2006).

lJyperforin and its analogues :inhibitCYP3A4 enaTme activit'y. Phyto-ch emi stry 67, 2550-6250.

Lewis, D. F. V. (2004). 57 varieties: the

human cytochrom es P 450 Pharm a

cogenomics 5, 305-318.Lewis, J. H., Ahmed, M., Shobassy, A,,

and Palese, C. (2006). Drug-ir rduced

liver disease. Curr, Opin. llattfoen-terol 22,223-233.

Li,M.,Ardrew, M. A.,Wang, J., Salinger,

D. H., Vicini, P, Grady, lL. W,Phillips, B., Shen, D. D., and r\nder-son, G. D. (2009). Effects of cran-berry juice on pharmacokineticsof beta-lactam antibiotics fbllow-ing oral administration. Antimicrob,Agents Chemother. 53, 27 25 -27 32.

Liang, Y, Xie, P, and Chan, K. (2004).

Quality control of herbal medicines.

J. Chrom ato gr. 812, 53-7 0.

Liao, H., Ma, T., Li, Y., Chen, I. T.,

and Chang, Y S. (2010). Concurrentuse of corticosteroids with Lir:orice-

containing TCM preparatic'ns inTaiwan: a National Health I:nsurance

Database Sttdy. I, Altern. Comple-

ment, Med.16,539-544.Liu, C. X., Yi, X. L., Si, D. Y, Xjao,

X. F., He, X., and Li, Y. Z. (2011).

Herb-drug interactions involvingdrug metabolizing enzyr.nes and

transporters. Cur. Drug Nlet,nb. 12,835-849,

Luyckx, Y A., and Naicker; S. (2008),

Acute kidney injury associaLted withthe use of traditional medicines. NatClin. Pract. Nephrol. 4, 664-41'L

Ma, X. H., Zheng, C. I., Han, L, Y.,

Xie, B., Jia, J., Cao, Z. W., Li, Y. X.,

and Chen, Y. Z. (2009). Slnergisticlhcrapeutic actions of herbal ingre-dients and their mechanis:ms frommolecular interaction and networkperspectives. Drug Discov.'foclay 14,

579-588.

Madabushi, R., Frank, B., Drerrelow,B., Derendorl H., and llutter-weck, V. (2006). Hypertiorin in

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research April 2012 l Volume 3 | Article 69 | 16

FasinLr et al Herb-drug interactions

St. [ohn's wort drug interac-tions, Errr. J, Clin, Pharnucol. 62,22:;-233.

Malati, C. Y, Robertson, S. M.,Hunt, J. D., Chairez, C., Alfaro,R. M., Kovacs, J. A., and Pen-zal:, S. R. (2011). Influence ofPanar ginseng on qtochrome P450(CYP)3A and P-glycoprolein (P-

gp,l activity in healthy partici-parrts. ,1. CIin. Phannacol. doi:I0.r 17 7 I 009127 001 14071 94. IEpubahearL ofprint].

Mann,:1, M. (2004). Drug interactionswilh lit John's wort: mechanisms andclirrical implications. Drug Saf. 27,

774;797.Marchetti, S., Mazzanti, R., and Beij-

nen, J. H. (2007). Concise review:clinical relevance of drug-drug andheilr-.drug interaction.s mediatedby the ABC transporter ABCBI(MDltl, P-glycop rotein). Oncologist

12,92,7-94t.Maridr:lss, M., and De Britto,A. l. (2008).

Onigins of plant derived medicines.

Eth.nobotanical Leqllets 12, 373-)87.Markell, M. S. (2010). "Herbal reme-

dies and the patient witb chronickidney disease," in Herbal Supple-

ment:t: Efficary, Toxicity, Interactions

wilh Western Drugs, and EJfects

on Cllinical Laboratory Tesfs. doi:10.10021 97 8047 09 101 08.ch6

Markowitz, l. S., DeVane, C L., Chavin,K. D., Taylol R. M., Ruan, Y., and

Donovan, I. L. (2003a). Effects ofgarlic (Allium sativan L) supplemen-tation on cytochrome P450 2D6 and3A,1 activity in healthy volunteers.CIin. Pharmacol. Ther.74, 170-177 .

Markowitz, J. S., Donovan,l. I, DeVane,

C. L,, Taylor, R. M., Ruan, Y.,

Wang, I. S., and Chavin, K. D.(2003b). Effect of St John's worton dlug metabolism by inductionof cy:ochrome P450 3A4 Enzyme.

JA /IA290,1500-1s04.

Martigncrni, M., Groothuis, G M. M.,ancl <le Kanter, R. (2006). Species

differences between mouse, rat, dog,

nonkey and human CYP-mediateddrug metabolism, inhibition andindoctiol. Exp ert Opin. Dru g Metab.

Toxicol.2,875-894.Marx, [., Pretorius, E., Espag, W J., and

Bester; M. J, (2005). Urginea san-guiinet nedicinal wonder or death

in rlisguise? Environ. Toxicol Phar-ma':ol, 20,26-34.

Marzolini, C., Paus, E., Buclin, T., and

Knr, R. B. (2004). Polpnorphismsin hu:man MDR1 (P-glycoprotern;:

recenl advances and clinical rele-

vance Clin. Pharmacol. Ther. 75,13-33.

Matsurnura, T., Alai, M., Yonemitsu,Y, lr4aruoka, D., Tanaka, T., Suzuki,

T., Yoshikawa, M., lmazeki, E, andYokosuka, O. (2010). The tradi-tiorral Japanese rnedicine rikkun-shito increases the plasma level ofghrelin in humans and mice. /. Gas-

troeflterol. 45, 300-307Meijerman,I., Beijnen, [. H., and Schel-

lenr;, I. H M. (2006) Herb-druginteractions irr oncology: focus onmechanisms of induction. Orcolo-gst 11,741\-752.

Merino, G., Perez, M., Real, R., Egidom,E., Prieto, J. G., and Alvarez, A.I. (2010). In vivo inhibition ofBCIIP/ABCG2 mediated tlansporto[ nitrofurantoin by the isoflavonesg(lnistein and daidzein: a compara-tive study in BCRP1 nice. Phatm.Res.27 ,2.098-?-105.

MettLlie, P, Husebye, E., Hustad,S. S., Lien, E. A., and Lovis,K. (2011). Grapefi'uit juice and

liquorice increase cortisol availabil-itlin patients with Addison's disease.

Eut. J. EndDcrinol 165,76I-769.Mitra, A. (20ft7). Alti.diabetic uses of

some comlrol herbs in tribal beltsof Midnapur (West) district of Ben-gtl. Ethno AtIe d I, 37 -.45.

Mochiki, E., )|anai, M., Ohno, T., andKurvano, H. (2010). The effect oftra-ditional Japanese medicine (Kampo)on gastroi:ntestiltal function. SurgToday40,l105-1111.

Mohamed, M. E., and Frye, R. F. (2010).IrLhibition of intestinal and hepaticgluc;uronidation of mycophenolica<:id by Gtinkgo biloba extract andflavonoids. Dtug Metab. Dispos.38,274-275.

Mohamed, lVt. ll., and Frye, R. E(20.t1a). Effects of herbal supple-ments on drug glucuronidationReview ol clinical, animal, and

in vitro sludies. Planta Med. 77,

3).1-327.Mohirmed, M,. Ii., and Frye, R. F.

(2011b), Irrhibitory effects of com-monly usecl herbal extracts on UDP-glucuronosyltransferase 1A4, 1A6,

arrd lA9 ,rn4/me activities. DrrgNl e t ab. D i syos. 39, 1 522 -1,528.

Mohirmmed, A. M. I., Jiang, X.,

Williams, 1,. lvl , Day, R. O., Roufo-galiri, B. D., Liauw, W. S., Xu, H., andM.clachlan, A, J. (2008). Pharma-codynn-i. hteraction of warfarinwitlr cranberry but not with garlicin healtlry subjects. B'r. l- Pharmacol.

15i4, t69l-1700.Mok, D. K. V/., and C.hau, F. (2006).

Chemical infornatir:n of Chineserneilicines: a challenge to chemist.

Chemomefiics httell Lab. Syst. 82,2tG-217.

Moortlry, R., Prabhu, K.1v4., and Murthy,P S. (2010). Mechanism of anti-diabetic action, efficacy and safety

profile of GII purified from fenu-greek (Tr igonella foenum- gracetLm

Linn.) seeds in diabetic animals.Indian l. Exp. Biol. 48,1119-1122.

Mu, Y., Zhang, J., Zhang, S., Zhou, H.H., Toma, D., Ren, S., Huang, L.,

Yaramus, M., Baum, A,, Venkatara-manan, R., and Xie, W. (2006).

Traditional Chinese medicines WuWei Zi (Schisandra chinensis Batll)and Gan Cao (Glycynhiza uralensis

Fisch) activate pregnane X receptorand increase warfarin clearance rnrats. J. Pharmacol. Exp. Ther, 316,

1369-1377.

Mukhtar, H. M., Ansari, S. H., Bhat,

Z. 4,, and Naved, T. (2006). Anti-hyperglycem ic activit1y ol Cyamops is

tetragonoloba. Beans on blood glu-cose levels in alloxan-induced dia-betic rats. Pharm. Biol. 44, 10-13.

Munday, R., and Munday, C, M. ( 1999).

Low doses ofdiallyl disulfide, a com-pound derived from garlic, increase

tissue activities of quinone reduc-tase and glutathione transferase inthe gastrointestinal tract of the rat.Nutr. Caflcet 34,42-48.

Murakami, Y., Tanaka, T., Murakami,l{., Tsujimoto, M., Ohtani, H.,and Sawada, Y (2006). Pharmaco-kinetic modelJing of the interac-tion between St John's wort andciclosporin A. 8r: /. Clin. Pharmacol.

61,67 t-676.Nabekura, T., Yamaki, T., Hiroi, T.,

Ueno, K., and Kitagawa, S. (2010).

Inhibition of anticancer drug efflutransporter P-glycoprotein by rose-

mary pbytochemicals. Pharmacol.

Res.61,259-263.Nagai, M., Fukamachi, T, Tsujimoto,

M., Ogura, K., Hiratsuka, A., Ohtani,H., Hori, S., and Sawada, Y (2009).

Inhibitory effects of herbal extracts

on the activity of human sulfotrans-ferase isoform sulfotrmsferase 1A3(SUfflA3). Biol. Philm. BuIL 32,

105--1 59.

Nakagawa, N., Katoh, M., Yoshioka, Y.,

Nakajima, M., and Y<rkoi, T. (2009).

Inhibitory effects of Kampo med-icine on human UGT2B7 activ-ity. Drug Metab. Pharmacokinet. 24,

490-499,Nebert, D. W., and Russell, D. W.

(2002). Clinical importance oftlre cytochrome P+50. Lancet 360,

I I 55-r 162.

Ni, W, Zhang, X., Wang, B., Chen,

Y, Han, H., Fan, Y., Zhou, Y, Tai,

G. (2010). Antitumor activities andimmunomodulatory effects ol gin-seng neutral polysaccharides in com-biration with 5-fltorouracl,. I. Med.

Food 13,270-277Nieminen, T. H., Hagelberg, N. M.,

Saari, T. I, Neuvonen, M, Laine,

K., Neuvonen, P. 1., and Olkkola,K. T. (2010). St ]ohn's wort greatly

reduces the concentrations of oraloxycodone. Eur, l, Pain 14, 854--859.

Nishikawa, M., Ariyoshi, N., Kotani, A.,Ishii, L, Nakamura, H., Nakasa, H.,Ida, M., Nakamura, H., Kimura, N.,Kimura, M., Hasegawa, A., Kusu,

F., Ohmori, S., Nakazawa, K., andKitada, M. (2004). Effects of contin-uous ingestion of green tea or grape

seed extracts on the pharmacokinetics of midazolam. Drug Metab.

Pharmacokinet. 19, 280-289.Nivitabishekam, S. N., Asad, M., and

Prasad, V S. (2009). Pharmaco-dlmamic interaction of Momordicacharantia with rosiglitazone in rats.

Chem. Biol. Interact. 177, 247-253.Norlin, M., and Wikvall, K. (2007).

Enzymes in the conversion ofcholes-terol into bile acids. Curr. MoL Med.

7, 199-218.Nowack, R. (2008). Review article:

cytochrome P450 en4me, andtransport protein mediated herb-drug interactions in renal trans-plant patients: grapefruit juice, St

fohn's wort - and beyond! Nephrol-ogy (Carhon) 13, 337-347.

Nutescu, I. A., Shapiro, N. L., Ibrahim,S., and West, P. (2006). Warfarin andits interactiouswith foods, herbs andother dietary supplements. ExpertOpin. Drug Saf. 5,433-451.

Ogbonnia, S., Adekunle, A. A., Bosa, M.K., and Enwuru,V N. (2008). Evalu-ation of acute and subacute toxicityol Alstonia congensls Engler (Apocy-

naceae) bark and Xlloph aethiopica(Dunal) A. Rich (Annonaceae) fruitsmixtures used in the treatmentof diabetes. Afr. l. Biotechnol. 7,

701-705Okada, K., Shoda, J, Kano, M., Suzuki,

S , Ohtake, N., Yamarnoto, M., Taka-

hashi, H,, Utsunomiya, H., Oda,

K., Sato, K., Watanabe, A., Ishii,T, Itoh, K., Yamamoto, M., Yokoi,

T., Yoshizato, K., Sugiyama, Y, and

Suzuki, H. (2007). Inchinkoto, a

herbal medicine and its irgre-dients dually exert Mrp2lMRP2-mediated choleresis and Nrf2-mediated antioxidative action in ratlsver. An. I. Physiol.292, G1450-Gr463.

Oluwatuyi, M., Kaatz, G. W., and Gib-bons, S. (2004) Artibacterial andresistance modifiTing activity of Ros-

marinus offcinalis PhyLochetnistry

65,3249-3254.Ono, A. E., Owo, O. I., Itam, E. H.,

and Konya, R. S. (2000). Blood pres-

sure depression by the fruit juice

of Carica papaya (L.) in renal and

DOCA-induced hypertension in therat Phytother. Res, 14, 235-239.

wwwfrontiersin.org April 2012 l Volume 3 | Article 69 | 17

Fasinu et al Herb-drug interactions

Ono, S, Hatanaka, T., Hotta, H , Satoh,

T., Conzalez, F. .1., Tsutsui, M. ( 199o).

Specifi city of substrate and inhibitorprobes for cy.tochrome P450s: eval-

uation of in vitro metabolism usingcDNA-expressed human P450 and

human liver microsomes. Xenobiot-ica 26,681-693.

Ozcakir, A., Sadikoglu, G., Bayram,

N., Mazicioglu, M M., Bilgel, N.,and Beyhan, I. (2007). Turkish gen-

eral practitioners and complemen-tarylalternative medicine. J. Ahern.Complem ent. MecL 13, 1,007 -1010.

Paine, M. F., Widmer, W. W., Pusek,

S. N., Beavers, K. L, Criss, A.B., Snyder, J., and Watkins, P B.

(2008). Further characterization ofa furanocoumarin-free grapefiuitjuice on drug disposition; studies

with ryclosporine Am. J. Clin, Nutr.87,863-87 L

Pal, D., and Mitra, A. K. (2006), MDR-and CYP3A4-mediated drug-herbalinteractions. Life Sci, 7 8, 213 l-2I45.

Palombo, E. A. (2006). Phytochemicalsfrom traditional medicmal plants

used in the treatment of diarrhoea:modes of action and effects on

intestinal function. Phytother. Rel20,7 L7-724.

Patanasethanont, D., Nagai, f., Yumoto,R., Murakmi, T., Sutthanut, K.,

Sripanidkulchai, B. O., Yenjai, C.,

and Takano, M. (2007). Effects ofKaempferia parviJlora extracts and

their flavone constituents on P-

glycoprotein function. I. Pharm. Sci.

96,223-233.Patel, M., Bessong, P, and Liu, IJ.

(2011). Traditional medicines, HIVand related infections: workshop 2C.

Adv. Dent. Res.23, 159-164.Patsalos, P, and Perucca, E. (2003). Clin-

ically important drug interactionsin epilepsy: interactions between

antiepileptic drugs and other drugs.

Lancet 2,+734478LPavek, P, and Dvorak, Z. (2008).

Xenobiotic-induced transcriptionalregulation of xenobiotic metabo-lizing enzymes of the cytochromeP450 superfamily in human extra-hepatic tissues. Curf. Dfug Metab.9,

r29-r43.Perucca, E. (2006) Clinically relevant

drug interactions with antiepilepticdrugs. Br. J. CIin. Pharmacol. 6I,246-255.

Pierard, S., Coche, J. C., Lantbier, P.,

Dekoninck, X., Lanthier, N., Rahier,

J., and Geubel, A. P (2009). Severe

hepatitis associated with the use ofblack cohosh: a report of two cases

and an advice for caution. Ear /.Gastro entercL Hepatol. 21, 941-9 45.

Piscitelli, S. C,, Burstein, A. H., Welden,

N., Gallicano, K. D., and Falloon,

J. Q002). The effect of garlic sup-plements on the pharmacokineticsof saquinavir. CIin. Infect. Dis. 34,23+-238.

Qi, Q. H., Wang, I., Liang, G. G.,

and Wu, X Z. (2007). Da-Cheng-

Qi-Tang prornotes the recoveryof gastrointestinal motility after

abdominal surgery in humans D1q.

Dis. Sci. 52, 1562-1570.

Quintieri, L., Palatini, P, Nassi, A.,Rtzza,P,, and Floreani, M. (2008).

Flavonoids diosmetin and tute-

olin inhibit midazolam metabolismby human liver microsomes and

recombinant CYP3A4 and CYP3A5

enzymes. Biochem. Pharmacol T5,

r426-1437Rannug, U., Agurell, E., Rannug, A.,

and Cederberg, H. (2006). Cer-

tain tryptophan photoproducts are

inhibitors of cytochrorne P450-

dependent mutagenicity. Environ.

Mol, Mutagen. 20, 289-29 6,

Roberts, D, and Flanagan, P. (2011).

Case report: cranberry juice and

warfarin. Home Healthc. Nurse 29,

92-97.Roby, C. A., Anderson, G., Kantor, E.,

Dryer, D. A., and Burstein, A. H.(2000). St Iohn's wort: effect onCYP3A4 activity. CIin. Pharmacol.

Ther. 67,451-457 .

Rogers, K. l, Grice, I. D., and

Griffiths, L. R. (2000). lnhibitionof platelet aggregation and 5-HTrelease by extracts of Australianplants used traditionally as headache

treatments, Eur. J. Pharm. Sci. 9,

355-363.Rostami-Hodjegan,A., and Tucker, G. T.

(2007). Simulation and prediction ofin vivo drug metabolism in humanpopulations from in vitro data. NatRev. Drug D iscor. 6, f 40-f 48.

Routledge, P. A, (2008). The European

herbal medicines directive: could ithave saved the lives of Romeo and

Ju\er? Drug Saf. 37, 416418.Saleem, T. S. M., Chetty, C. M.,

Ramkanth, S., Rajan,V S. T., Kumar,K. M., and Gauthaman, K. (2010).

Hepatoprotective herbs - a revrew.

Int. J. Res. Pharm. Sci,1,1-5.Sanderson, L T., Hordijk, J., Denison,

M. S., Springsteel, M. E, Nantz, IvI.

H., and van den Berg, M. (2004).

Induction and inhibition of aro-

matase (CYPI9) activity by nat-ural and spthetic flavonoid com-pounds in H295R human adreno-

cortical carcinoma cell. Toxicol. Sci.

82,70-79,Sarris, J., LaPorte, E., and Schweitzer,

I. (2011). Kava: a comprehensive

review of efficacy, safefy, and psy-

chopharmacology. Aust. N. Z. J, Psy-

chiatry 45,27-35.

Sawidou, S, Goulis, J., Giavazis, I,Patsiaoura, K., Fl,vtiroglou, P,and Arvanitakis, C. (2007). llerb-induced hepatitis by Teucrium

polium L.'. report of fwo cases andreview of the literature. Eur /.G a stroenterol. Hep ato L 19, 507 -.5II.

Saxena, A. K., and Panbotra, B.

R. (2003). Herbal remedies: renaltragedies. [ituiss Med. Wkh,. ],33,

1 88-189.Schoner, W (2000). Ouabain, a new

steroid horrnone of adrenal glandand hypothalamus. Exp. CIin.

Endocrinol. Diabetes. 108, 449-454.Scott, G. N., arLd Elrner, G W (2002).

Update on natural product .- druginteractions, Am l. Health Syst.

Pharm.59,339-347.Scott, M., Dinelrart, S. M., and Henry, L.

(2005) Dietarysuppkrments: altered

coagulation and effects on bruising.Dermatol. Srrg 31, 819-836.

Sevior, D. K., Hokkaleu, J., Toknen,A., Abass, K.., Tursas, L,, Pelkonen,

O., and Ahokas, l. T, (2010), Rapidscreening of comrner,;ially available

herbal products fbr the inhibitionof major human hepatic cytochrorreP450 enzynres using the N-in-oneco ckt aiI. Xe n o b i o ti c a til, 2 45 Z -,\ 45 4.

Sheeja, K., Shihab, P K., anrl Kut-tan, G. (2006), Antioxidant andanti-inflamrnatory activities of the

p\anl Andrographis p a nic ulata )\ees.lmmuno ph at m acol. I m muno t oxi col.

28,129-140.Shekelle, P G., I{ardy, M. L., Morton,

S. C., Maglione, M., Mojica, W A.,

Suttorp, M. I., Rhodes, S. L., f r rngvig,

L., and Gagnd, l. (2003). Efficacyand safety of ephedra and ephedrinefor weight loss and athletic perfor-mance. JAMA 289, \ 537 -|5 45

Sheweita, S. A., Newairy, A A., Man-sour, H A., anclYousef, M. I. (2002).

Effect of so:ne hypoglycemir: lierbson the activity ofphasr: I and II drug-metabolizing enzymes in alioxan-induced diabctic rats. Toxicology

174, 13r-r39.Shi,2., He, 1., Yao, T., Chang, W, Zhao,

M. (2005). Simultaneous determi-nation of cryptotanshinone, tanshi-none I and tanshinone IIA in tra-ditional Chinese medJcinal prepara-tions containing Radix Salvkt mibi-orrhiza by IIPLC. l. Pharm Biomed.

Anal 37,481-486.

Shukla, S., Zaher,H., Hartz, A., Bauer,

B., Ware, J. A., and Ambudlkar, S.

V. (2009). Curcumin inhibits theactivity of I\BCG2/BI3RP1, a mul-tidrug resislance-linked ABC drugtransporter in mice. I'harm. Iles.26,

480-487.

Singh, D., Kashyap,A., Pandey, R. V, and

Saini, K. S. (2011). Novel acLvances

in cytochrome P450 research. DrugDiscot. Today 16, 7 93-799.

Sousa, S A, Pascoa, H., Concei5ac, E. C ,

Alves, S. E, Diniz, D. G. A., Paula, J.

ll., and Bara, M. T. F. (2011). Disso-

lution test of herbal medicines con-taining Paullinia cupana: validationof methods for quantification and

assessmcnt of dissolution. Iraz. /.Pharm. Sci. 47, 269-277.

Spinella, M., and Eaton, L. A. (2002).

Hypomania induced by herbal andpharmaceutical psychotropic medi-cines following mild traumatir: braininjtry. Brain Inj. 16, 359-367

Stadlbauer, V, Fickert, P., Lackrer, C.,

Schmerlaib, J., Krisper, P, Trauner,

M., and Stauber, R. E. (200!i). Hepa-totoxicity of NONI juice: ret'ort oftwo cases. Worlcl J. Gdstroeflterol 11,

4758-6470.Stedman, C. (2002). Herbal hepatotox-

icity. Semin. Liver Dis,22, 195-206.

Steenkamp, V, and Stewart, M. (2005).

Nephrotoxicity associate,J withexposure to plant toxins, withparticular reference to Afri,ca. Ther.

D r r.g Mo nit, 27, 27 0-27 7.

Stewart, M. f., Steenkamp, V, viln der'

Merwe, S., Zuckerman, M,, and

Crowther, N. J. (2002). The cyto-toxic effects of a traditional Zuluremedy, impila (Callitepis laureola).IJum. Exp Toxicol. 21., 643447.

Suzuki, Y, Ito, Y., Konno, C., an<l Furuya,T (1991). Effects of tissue culturedginseng on gastric secretiol:r andpepsin activity. Yakugaku Zasshi 111,,

770-774,Szak6cs, G., V6radi, A., Ozvegy-l.aczka,

C., and Sarkadi, B. (20tt8). Therole of ABC transporters in drugabsorption, distribution, metabo-lisrn, excretion and toxicitF ('AIDME-

Tox). Drug Discot. Toda;v 13,

379-393.Szolomicki, S,, Samochowiec, L.., W6j-

cicki, |., and Drozdzik, M. (2000).

The influence of active contpDnents

of Eleutherococcus senticosus on cel-

lular defence and physical fitness inman. Phytother Res. I4. l0-35.

Sztajnkrycer, M. D., Otten, E. J., Bond,G. R., Lindsell, C. J., and coetz, R. J.

(2008). Mitigation of pennyrc,yal oilhepatotoicity in the mouse. Acad.

Energ. Med. 10, 1024-1028.Tachjian, A., Maria, V, and lahangir',

A (2010). Use of herbal productsand potential interactions irL patientswith cardiovascular diseases.,l, An.Coll. Cardiol 9, 515-525.

Taki, Y, Yokotani, K., Yamada, S., Shi-

nozuka, K., Kubota, Y., \Alatanabe,

Y, and Umegaki, K, (2012). Ginkgobiloba extract attenuates rvarfarin-mediated anticoagulation throughinduction of hepatic cytochrome

Frontiers in Pharmacology I Pharmaceutical Medicine and Outcomes Research Ap(il 2012 | Volume 3 | Article 69 | 18

Fasinu et al Herb-drug interactions

P450 enzymes by bilobalide in mice.

Phy ta me d.icine 19, 17 7 -182.Tam, S. W., Worcel, M., and Wyllie,

M, (2001). Yohimbine - a clin-iczrl review Pharmacol. Ther. 91,215-243.

Tamaki, H., Satoh, H., Hori, S,, Ohtani,H., a:nd Sawada,Y (2010). Inhibitoryeflects of herbal extracts on breast

cancer resistance protein (BCRP)

and structure-inhibitory potencyreJationship of isoflavonoids. DrugM,etab. Pharmacokinet. 25, 17 0-179.

Tang, i., Song, X., Zhu, M., and Zhang,

I. ('2009). Study on the pharmacoki-netic clrug-drug interaction poten-tial c'f Glyryrrhiza uralensis, a tradi-tio,nal Chinese medicine, witb lido-caiLne in rats. Phytother. Res 23,

603-607.Tang, I. C., Zhang, I. N., Wu, Y T.,

and Li, Z. X. (2006). Effect of thewater extract and ethanol exrracrfrom traditional Chinese medir:inesAngelica sinensis (Olii,.) Diels, Irgas-ticum chuanxiongHort and, RheunrpahnailtmL. oant liver cytochromeP450 activity, Phytother, Res. 20,r046-105 l.

Tannergren, C., Engman, H., Knutson,L., Hedeland, M, Bondesson, U., andLeLrnernds, H. (2004). St John's wortdecreases the bioavailability of R.

and li-veraparnil through inductionof the firstpass metabolism. Clin.

Ph a r m a col. Ther. 7 5, 298-309.Taylor, L, (2000). Plants B ased Drugs artd.

Medi cin es. Available at: http://w,rain-tree.com/plantdrugs.htm

[accessed November 03, 20 1 1 ].Teschl<e, R. (2010). Kava hepatotoxicity:

pathogenetic aspects and prospec.

tive considerations. Liver Int. 30,r2'74-1279

Tokita,'{., Yuzurihara, M., Sakaguchi,

M., Siatoh, K, and Kase, Y (2007).

The pharmacological effects ofDaik,:nchuto, a traditional herbalmedicine, on delayed gastrointesti-

nal transit in rat postoperative ileus.

J. Phormacol Scl. 104, 303-310.Tripathi, U. N., and Chandra, D.

(2010). Anti-hyperglycerric and

anrfi-r:xidative effect of aqueous

exlract of Montordica charantiapulp and Trigonella foenrm graecum

seed in alloxan-induced diabeticnts. Indian l. Biochem. Biophys.47,22"7-,233.

Ulbricht, C., Chao, W., Costa, D.,

Rusie -Seamon, E., Weissner, W., andWcrods, J. (2008). Clinical evidence

of herb-drug interactions: a system-

atir: review by the natural standardresea:rch collaborilion. Cur r. 7)rug

Me:tab. 9,1063-1 120.

Umr:Lara, K. I., and Camenisch, G.

(201 1). I.Tovel in vitro-in vivoextrapolation (IVIVE) method topredict he:patic organ clearance inrat. Phartn. Res. 29, 603-617.

van den Bout-van den Beukel, C. J.,

Flamza, O. f., Moshi, M. J., Matee,

M. I , Mikr, F., Burger, D M., Koop-mans, P P, Verweij, P. E , Schoonen,

W. G., and yan der \/en, A. J. (2008).

Fvaluatiorr of cJtotoxic, genotoxicanJ CYP450 enzyrnalic competitioneffects of Talzanian plant extracts

traditionally used for treatlrent offungal infections. Basic Clin. Phar-nt ocol. Tot ico L. I02, 5 15-526.

Van l(oon, .8. N., Flikrveert, S., leComte, M", Langendijk, P. N., Kwee-

Z.uiderwijl<, W J., Smits, P., and

Brouwers, J. R. (2005). Clinical rel-evance of drug-drug interactions -a slructured assessnellt procedure.

Drug Saf.'.',.8, I 131- 1 139.

Van Wy[<, B., Van Oudtshoorn, B., andGericke, N. (2009). Medicinal Plantso.f South tlfrica,2n<l Edn. Pretoria:Briza Publications, 1i36.

Vlachojannis, j., Cameron, M., and

Chrubasik, S, (2011). Drug interac-tions with St. John's wort products.I'harmacof. Res 63, 254-256.

Waako, P J., Smith, P., and Folb, PI, (2005). In vitro interactions ofAspilia africana (Pers.) C. D. Adams,

a tr aditional antimalarial medicinalplant, with artemisinin against Plas-

modium Jalciparutn. I. Ethnopharntacol. I02,262-268,

Wang, I F., and Chou, K. C. (2010).

N,lolecular modeling of cytochromeP4Ii0 and dmg metabolism. CanI)rug Meta b. IL, 3 42-3 46

Wang, I. F., Wei, D. Q,, and Chou, K. C.

(:2008). Drug candidates fi'om tradi-tional Chinese mediciues Curr.ToptrIed. Chem. 8, 165G-6i65.

Wang, Y, Shi, B., Cheng, Y, Xu, J., Jiang,C. F., and Xie, W Ii (2009). Drug-ilduced liver iLisease: an 8-year studyof patient{i fr<lm one gastroentero-

krgical delrartment, I. Dig. Dk. 10,

I 95-200.Wilasrusmee, C., Kittur, S., Siddiqui,

1., llruch, D., Wilas:rusnee, S, and

Kit'ur. D, S. (2002). Irr vitrommunom<ldtilatory effects of ten

commonly used herbs on murinellniplrocytes. jf. A,Itern. Complement.

Med. 8,46'.7-4'75

Wills, R. B H , Bone, ll., and Morgan,M. (2000), Herbal products: active

constituents, rnodes of action andqualify corrtrol. Nutr. Res. Rev. 13,47-.77 .

Wojcikowski, K., Wohlrnuth, H., Iohn-son, D. W., Rolfe, tr4., and Gobe, G.

(2009). An in vitro investigation ofherbs traditionally used for kidneyand urinary system disorders: poten-tial therapeutic and toxic effects.

Ne phr olo gy (Carlton ) 14, 7 0-7 9.

Wolf-Hall, C. (2010). "Fungal andmushroom toxins I' n Pathogens andToxins in Food: Challenges and Inter-ventions, eds V K. Juneja and J. NSofos (Washington, DC: ASM Press),

275-285.Wood, M. J., Stewilt, R. L,, Merry,

H., Iohnstone, D. E., and Cox, J,

t. (2003). Use of complementaryand alternative medical therapies inpatients with cardiovascular disease.

Am. Hear t J. 145, 806-812.Wu, C. L., Chiu, P F., Yang, Y., Wen,

Y. K., Chiu, C. C., and Chang, C.

C. (2011) Sustained low-efficiencydaily diafiltration with hemoperfu-sion as a therapy for severe star fruitintoxication: a report of two cases.

Ren. Fai\.33,837-841.Wu, W. W., and Yeung, I. H. (2010).

Inhibition of walfarin hydroxyla-tion by major tanshinones of Dan-shen (Salyia miltiorrhiza) in the ratin vitro and in vivo. Phytomedicine

17,219-226.Xu, L., Chen, Y, Pan, Y, Skiles, G.

L., and Shou, M. (2009). Predictionof human drug-drug interactionsfrom Linre-dependeut inactivationof CYP3A4 in primary hepatocytes

using a population-based simulator.Drug Metab. Disp os. 37, 2330-2339.

Yagmur, E., Piatkowski, A., Groger, A.,

Pallua, N., Gressner. A, M., and

Kiefer, P. (2005). Bleeding compli-cation under Gingko biloba medica-tion. An, J, I'Iematol, 79, 3 43-3 44.

Yao, W X., and Jiang, M. X. (2002).

Effects of tetrandrine on cardio-vascular electrophysiologic prop-erties- Acta Pharmacol. Sitt. 23,r069-t074.

Yap, K, Y, See, C. S., and Chan, A. (20 10).

Clinically-relevant chemotherapyinteractions with complementaryand alternative medicines in patientswith cancer. Recent Pat. Food Nutr.Agric.2, 12-55.

Yin, O. Q. P, Tomlinson, B,, and

Waye, M. M. Y (2004). Pharma-cogenetics and herb-drug interac-tions: experience with Ginkgo biloba

and omeprazoJe. Pharmacogenetics

14,841-850.Young, H. Y, Liao, j. C., Chang, Y S,

Luo, Y L., Lu, M C, and Peng, W.

H. (2006). Synergistic effect oI gin-ger andnifedipine on human plateletaggregation: a study in hypertensive

patients and normal volunteers. Afl.J. Chin. Med. 34, 545.-551.

Yu, C. P., Wu, P. P., Hou, Y C.,Lin, S. P, Tsai, S. Y, Chen, C. T,and Chao, P. D. (2011). Quercetinand rutin reduced the bioavailabil-ity of cyclosporine from Neoral, an

immunosuppressant, through acti-vating P-glycoprotein and CYP 3A4.

J. Agric. Food Cheffi.59,4644=4648.

Zhang, X. (2002). Effect on gas-

trointestinal functions of Polygonumpaleaceum. Zhong Yao Cai 25,r92-r93.

Zhang, 2., and Wong, Y. N. (2005).

Enzyme kinetics for clinically rel-evant CYP inhibition. Cun. DrugMetab. 6,2+I-257 .

Zhou, S., Lim, L. Y., and Chowbay, B.

(2004). Herbal modulation of P-

glycoprotein. Drug Metab. Rev.36,

57-104.Zhou, S. F. (2008). Drugs behave as sub-

strates, inhibitors and ilducers ofhuman cy.tochromeP450 3A4. Curr.

Drug Metab,9,31V322.Zhu, 8., Sun, Y, Yun, X., Han, S.,

Piao, M. L., Murata, Y, and Tada,

M. (2004). Resistance imparted bytraditional Chinese medicines tothe acute change in glutarric pyru-vic transaminase, alkaline phos-phatase and creatine kinase activi-ties in rat blood caused by blood.Biosci. Biotechnol Biochem. 68,1 1 60-1 163.

Ziment, I., and Thshkin, D. P (2000).

Alternative medicine for allergy and

asthma. /. Allergy Clin, Lnmunol.106,603-614.

Conflict of Interest Statementi Theauthors declare that the research was

conducted in the absence of any com-mercial or financial relationships thatcould be construed as a potential con-flict of interest.

Receiyed: 20 Decenrber 2011; accepted:

05 April 2012; published online: 30 April2012.

Cil:ation: Fssinu PS, Bouic PJ and

Rosenkranz B (2012) An overview of the

eyidence and mechanisms of herb-druginteractions. Front. Pharmacol 3:69. doi:

1 0. 3 3 8 9 / fph at. 20 t 2. 000 69

This artirle was submitted to FronLiers

in Pharmaceutical Medicine and Out-cotnes Research, a specialty of Frontiers

in Pharmacology.

Copyright @ 2012 Fuiru, Bouic and

Rosenkranz. This is an open-access qrticle

distributed under the tetms of the Cre-

ative Commons Attribution Non Com-

mercial License, which permits non-

commercial use, distributiotr, and repro-

duction in other forunts, provided the

original authots arul source are credited.

www.fiontiersin.org April 2012 | Volume 3 | Article 69 | 19