Drug Interactions with Herbal Medicines

Home , Amentoflavone, Bilobalide, Cilostazol, Desmethoxyyangonin, Dihydromethysticin, Flavokavain

Shaojun Shi^ and Ulrich Klotz^'^ 1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China 2 Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany 3 University of Tuebingen, Tuebingen, Germany

Contents

Abstract 78 1, Mechanisms of Herbal Medicine-Drug Interactions 79 1.1 Inhibition of Cytochrome P450 (CYP) 79 .,2 Induction of CYP , 79 .,3 Inhibition or Induction of Drug Transporters 79 2, Evaluation of Herbal Medicine-Drug Interactions 80 2.1 Black Cohosh 80 2.1.1 In Vtfro and Animal Studies 80 2.1.2 Clinical Studies \ 80 2.2 Echinacea 80 2.2.1 In Vitro and Animal Studies 80 2.2.2 Clinical Studies 86 2.3 Garlic 86 2.3.1 In V/fro and Animal Studies 86 2.3.2 Clinical Studies 87 2.4 Ginkgo 87 2.4.1 In Vitro and Animal Studies 88 2.4.2 Clinical Studies _ 88 2.5 Goldenseal 89 2.5.1 In Vitro and Animal Studies 89 2.5.2 Clinical Studies 89 2.6 Kava 90 2.6.1 In Vitro and Animal Studies 90 2.6.2 Clinical Studies 90 2.7 Milk Thistle 90 2.7.1 In Vitro and Animal Studies 90 2.7.2 Clinical Studies ,' 91 2.8 Ponax ginseng , 92 2.8.1 In Vitroanó Animal Studies 92 2.8.2 Ciinical Studies 92 2.9 Ponax quinquefolius 92 2.9.1 Animal Studies , 93 2.9.2 Clinicai Studies 93 2.10 Saw Palmetto 93 2.10.1 In Vitroand Laboratory Studies 93 2.10.2 Ciinical Studies • 93 2.11 St John's Wort 93 78 Shi & Klotz

2.11.1 In V/fro and Animal Studies 93 2.11.2 Ciinical Studies 94 3. Conciusions 95

AbStrQCt In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine- drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.

Herbal medicine - also called botanical medicine, medical her- and/or pharmacodynamic interactions involving 11 common balism, phytotherapy or phytomedicine - refers to use of various herbal medicines, which are all widely used in the Western parts of a plant (seeds, berries, roots, leaves, bark or flowers) for medicinal purposes. Herbal medicines have been widely used The databases MEDLINE, Embase and the Cochrane Library for a variety of conditions over thousands of years, and they were searched from their inception to June 2011, using the following have gained increasing popularity especially over the last dec- terms: 'herbal medicine', 'botanical medicine' and 'phytotherapy', ade. Furthermore, they are often administered in combination in combination with 'drug interactions', 'adverse drug reaction', with conventional drugs, raising the potential for pharmaco- 'safety', 'toxicity', 'pharmacokinetics' and 'pharmacodynamics'. kinetic and/or pharmacodynamic interactions.''"''1 There has The names and primary active constituents of the 11 common herbal been increasing concern about their safety, potential toxicity medicines were .also used as keywords. No language restrictions and interactions with other drugs.f^"''*' were imposed. Review articles were retrieved and searched to In general, herbal medicines are considered traditional identify additional relevant primary research articles. Clinical health aids, which are currently not subject to the same scrutiny studies in human were all included and emphasized. and regulatory processes that apply to conventional and over- In vitro screening techniques and animal models play a major the-counter medicines. Manufacturers are exempted from pre- role in identifying possible herbal medicine-drug interactions market safety and efficacy testing before releasing a herbal and thus could be used to initiate clinical studies. Therefore, medicine and from any post-marketing surveillance.f'^' Ad- data from in vitro and animal studies were also included to ditionally, the use of herbal medicines is complicated by a explore the mechanisms of herbal drug interactions, which were variety of factors, including lack of scientific evidence of safety generally excluded from several previous reviews. One should and efficacy, lack of regulatory oversight, lack of quality con- be aware that extract constituents from herbal medicines might trol and lack of knowledge about herbal medicine-drug inter- have some confounding effects. Some extract constituents avail- actions among patients and health care providers, as well as able in the in vitro tests are neither bioavailable nor relevant under-reporting and underestimation of adverse effects.^'^-'^^ to the in vivo situation. For example, tannins can denature pro- Therefore, there is an urgent need to better understand the teins and produce irrelevant in vitro results. Many ñavonoids are mechanisms of potential herbal medicine-drug interactions and only present in vivo in the form of their conjugates, whereas they to provide more current information for clinical practice. The are present in the plant extracts in the form of their genuine present review provides evidence of potential pharmacokinetic glycosides.

Furthermore, polymorphisms of genotypes, specifically petition for the reactive site of the enzyme.P^l Herbal medicines those found in certain ethnic groups, may influence herbal sometimes inhibit CYP enzymes in a competitive/noncompetitive medicine-drug interactions mediated through metabolic and mixed manner, depending on the CYP species and the herbal transport pathways. Therefore, the effects of pharmacogenetics constituents.'^-'-^''] Irreversible inhibitors usually covalently mod- on the safety and risks of herbal medicines and co-administered ify an enzyme, and therefore inhibition cannot be reversed. drugs are also reviewed and discussed. However, not all irreversible inhibitors form covalent adducts with their enzyme targets. Some reversible inhibitors bind so 1. Mechianisms of Herbal Medicine-Drug interoctions tightly to their target enzymes that they are essentially irreversible. Compared with reversible inhibition, mechanism-based As with any drug interaction, herbal medicine-drug inter- (suicide) inhibition or irreversible inhibition of CYP isoforms, actions can be explained by pharmacokinetic and pharmaco- particularly CYP3A4, by herbal medicine is characterized by dynamic mechanisms. Pharmacodynamic interactions occur time-, concentration- and NADPH-dependent blockade.P-^^-^^l when the pharmacological action of a herbal medicine sy- This type of inhibition can completely inactivate the metabo- nergizes, augments or antagonizes the biological activity of a lism of other drugs and may persist even after withdrawal of conventional drug.'''^ Although most herbal medicine-drug in- herbal medicines.P^'-^*' teractions are likely to be negative in nature, it is important to realize that a few interactions may have a beneficial effect by increasing drug efficacy or diminishing potential side effects. 1.2 induction of CYP For example, combined therapy with garlic (250mg/kg) and captopril demonstrated greater synergistic interaction with re- Induction of CYP is characterized by promotion of gene spect to the fall in blood pressure and angiotensin-converting activation or messenger RNA (mRNA) synthesis or inhibition enzyme inhibition.t'^1 Silymarin (140 mg three times daily) in of degradation of protein or mRNA.'^^' Induction is a slow combination with desferrioxamine can be safely and effectively regulatory process in contrast to the immediate response of CYP used in the treatment of iron-loaded patients as it has been inhibition.'-'") The most prominent mechanisms for CYP induc- shown to have beneficial effects in thalassaemia patients.'"' tion are ligand-dependent transcription activation of nuclear The vast majority of potential herbal medicine-drug interac- receptors, such as pregnane X receptors (PXR), constitutive tions are of pharmacokinetic origin, resulting in changes in androstane receptors (CAR) or aryl hydrocarbon receptors absorption (e.g. modulation of efflux and uptake transporters, (AhR).'3'-34] Species differences in CAR and PXR activation complex formation, gastrointestinal motility and pH) and bio- make the clinical prediction of CYP induction difficult.'^'''^^^ transformation (e.g. inhibition or induction of drug-metabolizing Herb-mediated inductive effects on CYP isoforms have been of enzymes) of the affected drug. Pharmacokinetic interactions concern for CYP3A, CYP2B6 and CYPl A2, and may result in become clinically significant when considerable changes occur subtherapeutic plasma concentrations leading to reduced effi- in pharmacokinetic parameters (e.g. the area under the plasma cacy of the drug, or even treatment failure. concentration-time curve [AUC], the maximum plasma concentration [Cmax] or the elimination half-life [t ./J) of prescrip- 1.3 inhibition or induction of Drug Transporters tion medications, especially those with a narrow therapeutic index, such as warfarin and digoxin.''"^1 In recent years, many drug transporters have been identified The following sections will focus on pharmacokinetic inter- in humans. The best characterized transporter is P-glycoprotein actions involving inhibition or induction of cytochrome P450 (P-gp), the product of the MDRl gene (now known as ABCBl), (CYP) and/or drug transporters.['"^•^°1 which functions as a drug efflux pump. P-gp is located on the apical membrane of cells in the gastrointestinal tract, liver, 1.1 Inhibition of Cytochrome P450 (CYP) kidney, lung, blood-brain barrier and placenta.'^*! Within intestinal enterocytes, the role of P-gp is to actively secrete some Inhibition of drug-metabolizing enzymes can be simply clas- absorbed drugs back into the intestinal lumen. Therefore, in- sified into reversible and irreversible inhibition, on the basis of the hibition or induction of P-gp by herbal medicine can result in underlying mechanism.P'l Reversible inhibition is most common elevated or reduced drug concentrations, respectively. Like- and can be further divided into competitive, noncompetitive and wise, induction of P-gp appears to be regulated by the nuclear uncompetitive inhibition. The most frequent type is simple com- receptors PXR or 'l

It has been observed that many drugs and herbal active mouse PXR was involved in the induction of CYP3A11, but the constituents are co-substrates for both P-gp and CYP3A4. In human counterpart was not.t^^' In addition, black cohosh ex- addition, P-gp and CYP3A4 constitute a highly efficient barrier tracts (75% and 80% ethanol) can inhibit several CYP iso- for the bioavailability of many orally absorbed drugs.t^'"'''^ The enzymes (1A2, 2D6, 2C9, 3A4) in vitro and thus may have the interdependence of both drug metabolism and transport on the potential to induce herb-drug interactions.''"'^] disposition of drugs has gained considerable attention and is termed 'transport-metabolism interplay'.i'*^'''^^ Therefore, it is 2.1.2 dinicai Studies sometimes difficult to evaluate the specific role played by each Four studies evaluated the potential interactions of black co- of these two different mechanisms in changing the bioavail- hosh with the probes midazolam (CYP3A4/5 substrate), caffeine ability and disposition of co-administered drugs. (CYP1A2), chlorzoxazone (CYP2E1), debrisoquine (CYP2D6) and digoxin (P-gp).'''^""'''! In 12 healthy volunteers treated with 2. Evaluation of Herbal Medicine-Drug Interactions black cohosh 2180 mg/day for 28 days (a dose substantially higher than the usual daily dose), weak (approximately 8%) inhibition of Potential herbal medicine-drug interactions have been reported CYP2D6 appeared to be of no clinical relevance.'*^! Likewise, no in a wide variety of laboratory, animal and human studies. Fur- effects on CYP3A4/5, CYP1A2 or CYP2A1 were found.''*^-'*'! thermore, herbal medicines have been shown to interact clinically Similarly, in 16 healthy volunteers receiving black cohosh with many conventional drugs (see table I). In the following sec- 80 mg/day for 14 days, CYP2D6 activity was not affected.'"^! Fi- tions, we will provide some examples of how herbal medicines nally, in 16 healthy volunteers receiving black cohosh 40 mg/day affect the pharmacokinetic and/or pharmacodynamic profiles of for 14 days, no significant effects on digoxin pharmacokinetics conventional medications. were observed, suggesting no influence on P-gp function.'''^ The results have shown that co-administration of black 2.1 Black Cohosh cohosh hardly affects CYPs or P-gp. However, further studies Black cohosh (Actaea racemosa) is one of the most frequently in humans are needed to demonstrate the safety of concomitant used herbal medications for menopausal vasomotor symp- use of black cohosh and conventional drugs. toms.t'^'i Recently, a 'potential association' between black cohosh and hepatotoxicity has been suspected in Australia, Canada and 2.2 Echinacea Europe. However, one critical analysis demonstrated no causal relationship between black cohosh treatment and the observed Echinacea is an unspeciflc immunostimulant mainly used to liver disease.''^^1 Likewise, a recent meta-analysis of five ran- treat and prevent infections of the upper respiratory tract, such domized controlled clinical trials involving a total of 1117 as the common cold and influenza.''^^^ Echinacea purpurea (L) women and a critical review suggested that black cohosh had no Moench, Echinacea angustifolia (DC) Hell and Echinacea pal- adverse effects on liver function.['''^•''''*i Furthermore, the lida (Nutt) Nutt represent the three main species. They possess Dietary Supplement Information Expert Committee of the US phytochemical similarities, of which alkylamides are thought Pharmacopeia's Council of Experts outlined that pharmaco- to be the chemical moieties responsible for any modulation of kinetic and toxicological data did not reveal unfavourable CYP information about black cohosh. Nevertheless the committee recommended that black cohosh products should be labelled 2.2.1 in Vitro and Animal Studies with a statement of caution.''^^^ As black cohosh can induce Conflicting results have been reported regarding the impact of hypotension, potential pharmacodynamic interactions may occur Echinacea on CYP activity. Echinacea extracts and alkylamides when it is taken with anaesthetics, antihypertensives or sedatives. can inhibit CYP3A4 activity with considerable variation in potency, depending on the model substrate that is used.''^""'^''! 2.7.7 in Vitro and Animal Studies Weak inhibition of CYP3A4 activity with the probe 7-benzyl- Some preclinical studies have investigated the influence of oxy-4-trifluoromethylcoumarin was observed, but in the pre- black cohosh or its extract constituents on CYP.'^^''^^^ Mice sence of the model substrate resorufin benzyl ether, mild treated with black cohosh 500mg/kg for 28 days showed that he- induction was seen. A minor effect on CYP2D6 and moderate patic CYP3A11 was induced 7-fold, but no difference was found in inhibition of CYP2C9 was noted with E. purpurea.^^^'*^ the small intestine and kidney, suggesting that upregulation of In cultured primary human hepatocytes, E. purpurea CYP3A11 by black cohosh was liver specific. Interestingly, (4.74^73.5 (ig/mL) was able to inhibit CYP1A2, CYP2D6

Table I. Summary of clinical herbal medicine-drug interactions

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References Black cohosh Caffeine No effect on caffeine pharmacokinetics None 44 Chiorzoxazone No effect on chiorzoxazone pharmacokinetics None 44 Debrisoquine Mixed results. Increased debrisoquine urinary Weak inhibition 44,45 recovery ratios by 7%; no effect in another trial of CYP2D6 Digoxin No effect on digoxin pharmacokinetics None 46 Midazoiam No effect on midazoiam pharmacokinetics None 44.47

Echinacea Caffeine Mixed results. Reduced oral clearance of caffeine; Inhibition of CyP1A2 48,49 no effect in another trial

Chiorzoxazone No effect on chiorzoxazone pharmacokinetics None 48 Darunavir No effect on darunavir pharmacokinetics None 50 Debrisoquine No effect on debrisoquine pharmacokinetics None 45,48 Dextromethorphan No effect on dextromethorphan pharmacokinetics None 49 Digoxin No effect on digoxin pharmacokinetics None 51 Fexofenadine No effect on fexofenadine pharmacokinetics None 52 Midazoiam Mixed results. Increased systemic clearance and Induction of hepatic 48,49,52 oral bioavailability of midazoiam; no effect In one trial; CYP3A and inhibition decreased midazoiam AUC and increased oral of intestinal CYP3A clearance of mldazolam in another trial Lopinavir No effect on lopinavir pharmacokinetics None 52 Ritonavir No effect on ritonavir pharmacokinetics None 50,52 Tolbutamide No effect on tolbutamide pharmacokinetics None 49 Warfarin Slightly increased clearance of S-warfarin; no Weak induction of 53 effect on warfarin pharmacodynamics CYP2C9

Garlic Alprazolam No effect on alprazolam pharmacokinetics None 54 Caffeine No effect on caffeine pharmacokinetics None 55,56 Chiorzoxazone Decreased 6-hydroxychlorzoxazone/chlorzoxazone Inhibition of CYP2E1 55-57 serum ratios Ciclosporin No effect on ciclosporin pharmacokinetics None 58 Debrisoquine No effect on debrisoquine pharmacokinetics None 55,56 Dextromethorphan No effect on dextromethorphan pharmacokinetics None 54 Docetaxel No significant effect on docetaxel pharmacokinetics None 59 Fluindione Decreased INR Unknown 60 Midazoiam No effect on midazoiam pharmacokinetics None 55,56 Paracetamol No effect on paracetamol pharmacokinetics None 61 (acetaminophen) Pravastatin No effect on pravastatin pharmacokinetics None 62 Ritonavir No effect on ritonavir pharmacokinetics Unknown 63 Saquinavir Decreased saquinavir AUC and C^ax Induction of P-gp 62,64 Simvastatin No effect on simvastatin pharmacokinetics None 62 Warfarin One case report of increased INR; no effect on None 65-67 warfarin pharmacokinetics or pharmacodynamics

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Tabie I. Contd Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References Ginkgo biloba Alprazolam Decreased alprazolam AUC Weak inhibition 68 of CYP3A4 Bupropion No effect on bupropion pharmacokinetics None 69 Caffeine No effect on caffeine pharmacokinetics None 55,56 Chlorzoxazone No effect on chlorzoxazone pharmacokinetics None 55,56 Cilostazol No enhancement of antiplatelet activity; can Unknown 70 potentiate the bleeding time prolongation effect of cilostazol Clopidogrel No enhancement of antiplatelet activity None 70 Debrisoquine No effect on debrisoquine pharmacokinetics None 55,56 Dextromethorphan No effect on dextromethorphan pharmacokinetics None 68 Diazepam No effect on diazepam pharmaookinetics None 71 Diclofenac No effect on diclofenao pharmacokinetics None 72 Digoxin No significant effect on digoxin pharmacokinetics None 73 Donepezil No effect on donepezil pharmacokinetics None 74 Fexofenadine Mixed results. Increased plasma concentrations of Probable inhibition 75,76 fexofenadine; no effect in another trial of P-gp Flurbiprofen No effect on flurbiprofen pharmacokinetics None 77 Lopinavir No effect on lopinavir pharmacokinetics None 75 Metformin No effect on metformin pharmacokinetics None 78 Midazolam Mixed results. No effect on midazolam Unknown 55,56,75,79 pharmacokinetics; increased midazolam AUC in one trial; decreased midazolam AUC and Cmax i" another trial Nifedipine No effect on nifedipine pharmacokinetics None 80 Omeprazole Decreased plasma concentrations of omeprazole Induction of CYP2C19 81 and omeprazole sulfone Ritonavir No effect on ritonavir pharmacokinetics None 75 Talinolol Increased talinolol Cmax and AUC Inhibition of P-gp 82,83 Ticlopidine No significant effect on ticlopidine pharmacokinetics None 84-86 Tolbutamide Mixed results. Decreased tolbutamide AUC; Possible effect on CYP2C9 72,79 no effect in another trial Voriconazole No significant effect on voriconazole pharmacokinetics None 87 Warfarin No significant effect on warfarin pharmacokinetics or None 88 pharmacodynamics

Goldenseal Caffeine No effect on caffeine pharmacokinetics None 44 Chlorzoxazone No effect on chlorzoxazone pharmaookinetics None 44 Ciolosporin Increased blood concentration of ciclosporin Inhibition of CYP3A4 89,90 Debrisoquine Decreased 8-hour debrisoquine urinary recovery ratios Inhibition of CYP2D6 44,45 Digoxin No significant effect on digoxin pharmacokinetics None 91 Indinavir No significant effect on indinavir pharmacokinetics None 92 Midazolam Increased midazolam AUC and C^ax Inhibition of CYP3A4/5 44,93

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Table I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References Kava Alprazolam Coma (lethargy, disorientation) Additive effect on 94 GABA receptor Caffeine No effect on caffeine pharmacokinetics None 44 Chlorzoxazone Decreased 6-hydroxychlorzoxazone/chlorzoxazone Inhibition of CYP2E1 44 serum ratios

Debrisoquine No effect on debrisoquine pharmacokinetics None 44,45 Digoxin No significant effect on digoxin pharmacokinetics None 91 Levodopa Reduced efficacy None 94 Midazolam No effect on midazolam pharmacokinetics None 44,93

Milk thistle Caffeine No effect on caffeine pharmacokinetics None 48 Chlorzoxazone No effect on chlorzoxazone pharmacokinetics None 48 Debrisoquine No effect on debrisoquine pharmacokinetics None 45,48 Desferrioxamine Beneficial effects Unknown 19 Digoxin No significant effect on digoxin pharmacokinetics None 46 Indinavir No significant effect on indinavir pharmacokinetics None 95-97 Irinotecan No significant effect on irinotecan pharmacokinetics None 98 Losartan Increased losartan AUC; decreased metabolic inhibition of CYP2C9 99 ratio of losartan

Metronidazole Increased clearance of metronidazole; Induction of both intestinal 100 decreased t,,^, C^ax and AUC P-gp and CYP3A4 Midazolam No effect on midazolam pharmacokinetics None 47,48 Nifedipine No significant effect on nifedipine pharmacokinetics None 101 Ranitidine No effect on ranitidine pharmacokinetics None 102 Rosuvastatin No significant effect on rosuvastatin None 103 pharmacokinetics

Talinolol Increased talinolol C^ax and AUC; Inhibition of P-gp 104 decreased talinolol oral clearance

Ranax ginseng Caffeine No effect on caffeine pharmacokinetics None 55,56 Chlorzoxazone No effect on chlorzoxazone pharmacokinetics None 55,56 Debrisoquine Weak or no effect on debrisoquine Weak or no effect 55,56 pharmacokinetics on CYP2D6 Midazolam No effect on midazolam pharmacokinetics None 55,56 Nifedipine Increased plasma concentration of nifedipine Unknown 105 Warfarin No effect on warfarin pharmacokinetics None 106-108 or pharmacodynahiics

Panax Indinavir No effect on indinavir pharmacokinetics None 109 quinquefoHus

Warfarin Reduced anticoagulant effect of warfarin None 110 Zidovudine No effect on zidovudine pharmacokinetics None 111

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Table I. Contd Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References Saw palmetto Alprazolam No effect on alprazolam pharmaookinetics None 112 Caffeine No effect on caffeine pharmacokinetics None 48 Chlorzoxazone No effect on chlorzoxazone pharmacokinetios None 48 Debrisoquine No effect on debrisoquine pharmacokinetics None 48 Dextromethorphan No effect on dextromethorphan pharmacokinetics None 112 Midazolam No effect on midazolam pharmacokinetics None 48

St John's wort Alprazolam Mixed results. Decreased alprazolam AUC and l^; Induction of CYP3A4 113-115 weak or no effect in two trials Amitriptyline Decreased amitriptyline AUC Induction of CYP3A4 or P-gp 116 Atorvastatin Reduced efficacy of atorvastatin I nduction of CYP3A4 and P-gp 117 Bupropion Decreased bupropion AUC Induction of CYP2B6 118 Buspirone Serotonin syndrome Additive effect on serotonin 119 reuptake Caffeine Mixed results. No effect on caffeine pharmacokinetics; None 55,56,113,120-122 increased metabolic ratios only in females in one trial Carbamazepine Mixed results. Decreased pseudohypericin AUC; Induction of CYP3A4 123,124 no effect on carbamazepine pharmacokinetics in another trial Chlorzoxazone Increased 6-hydroxychlorzoxazone/chlorzoxazone Induction of CYP2E1 55,56 serum ratios Cimetidine Increased hypericin AUC Inhibition of CYP3A4 124 Ciclosporin Decreased ciclosporin AUC and Câx Induction of CYP3A4 and/or 125-128 P-gp Debrisoquine No effect on debrisoquine pharmacokinetics None 45,55,56,129 Dextromethorphan No effect on dextromethorphan pharmacokinetios None 114,115,120,121 Digoxin Mixed results. Decreased digoxin AUC and Câxl no Induction of P-gp 51,113,130-132 effect in one trial using a low-dose hyperforin extract Erythromycin Increased erythromycin metabolism Induction of CYP3A4 130 Fexofenadine Mixed results. Decreased fexofenadine plasma Induction of P-gp 125,133,134 concentration; increased fexofenadine Câx after single dose Finasteride Decreased finasteride AUC, Câx and ty^ Induction of CYP3A4 135 Fluoxetine Serotonin syndrome Additive effect on serotonin 136 reuptake Gliclazide Decreased gliclazide AUC and ti^; Unknown 137 increased apparent clearance Ibuprofen No effect on ibuprofen pharmacokinetics None 138 Imatinib Decreased imatinib AUC, Câx and ti^ Induction of CYP3A4 139-141 Indinavir Decreased indinavir AUC Induction of CYP3A4 142 Irinotecan Decreased plasma concentrations of the active Induction of CYP3A4 143 metabolite SN-38 Ivabradine Decreased ivabradine AUC and Câx Induction of CYP3A4 144

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Table I. Contd

Herbal medicine Conventional drug Clinical outcomes of interaction Possible mechanism References Mephenytoin Increased urinary 4'-hydroxymephenytoin Induction of CYP2C19 122 excretion

Methadone Decreased methadone blood concentrations; Induction of CYP3A4 or P-gp 145 induced withdrawal symptoms Midazolam Mixed results. Decreased midazolam AUC; Induction of CYP3A4 (primarily weak effect in two trials with low hyperforin content; intestinal) 55,56,121,125,134 no effect with short-term administration in one trial 146-148 Mycophenolic acid No effect on mycophenolic acid pharmacokinetics None 149 Nevirapine Decreased nevirapine plasma concentration Induction of CYP3A4 150,151 Nifedipine Decreased nifedipine AUC Induction of CYP3A4 152 Omeprazole Decreased omeprazole AUC and Câx Induction of CYP3A4 and 153 CYP2C19 Oral contraceptive Mixed results. Increased metabolism of oral Induction of CYP3A4 154-158 contraceptive and reduced efficacy; no effect in one trial using a low-dose hyperforin extract Pravastatin No effect on pravastatin pharmacokinetics None 159 Prednisone No significant effect on prednisone pharmacokinetics None 160 Ouazepam Decreased quazepam AUC and Câx Induction of CYP3A4 161 Ritonavir Increased midazolam AUC when co-administered Predominant CYP3A4 inhibition 162 with St John's wort and ritonavir Simvastatin Decreased plasma concentration of simvastatin Induction of CYP3A4 159 Talinolol Decreased talinolol AUC Induction of intestinal P-gp 163 Tacrolimus Decreased tacrolimus AUC; increased apparent Induction of CYP3A4 and P-gp 149,164 oral clearance Theophylline Mixed results. No significant effect on theophylline None 165,166 pharmacokinetics; decreased theophylline plasma concentration in one case report Tolbutamide No effect on tolbutamide pharmacokinetics None 113,121 Verapamil Decreased verapamil AUC and Câx Induction of intestinal CYP3A4 167 Voriconazole Increased voriconazole AUC 10 hours after Modulation of CYP2C19 168,169 administration; decreased voriconazole AUC on day 15 Warfarin Increased apparent clearance of warfarin; Induction of CYP3A4 106 decreased INR Zolpidem Decreased zolpidem AUC and Câx Induction of CYP3A4 170 AUC=area under the plasma concentration-time curve; Câx = maximum plasma concentration; CYP = cytochrome P450; GABA=gamma-aminobutyric acid; INR = international normalized ratio; P-gp = P-glycoprotein; ti^=elimination half-life,

and CYP3A4, but CYP2C19 and CYP2E1 were not affected. In addition, E. purpurea can inhibit P-gp activity.''^^' In intestinal Importantly, the inhibitory potency was dependent on the al- Caco-2 cells, E. purpurea (from 0.4 to 6,36 mg dry weight/mL) dimin- kylamide content.t'^^"'^^! However, E. purpurea alkylamides ished P-gp activity in a dose-dependent manner,''^'' In the hu- showed significant inhibition of CYP2E1 at concentrations as man proximal tubule HK-2 cell line, N-hexane root extracts from low as 25 nmol/L,['^^] Ethanolic extracts oiEchinacea containing E. pallida, E. angustifolia and E. purpurea were able to reduce P-gp 3.7% polyphenolic compounds can also both inhibit the ex- activity, and E. pallida was the most active species.''^^^ In human pression of CYP3A1/2 and induce CYPlAl and embryonic kidney 293 cells, 270 ng/mL of an E. purpurea extract

inhibited the infltix of another transporter protein, organic anion- sclerosis, and a variety of other conditions such as cancer, be- transporting polypeptide (OATP)-B, by 55.5%.'"^' Overall, E. pur- cause it is believed to have antimicrobial, anticancer and purea is likely to inhibit drug transport by P-gp and other transporters. antioxidant activities, and to improve immune function. The major constituents of garlic are organosulfur compounds (e.g. 2.2.2 Clinical Studies allicin and alliin), which are responsible for the suggested In 12 healthy subjects receiving 1600 mg/day of E. purpurea root beneficial biological effects.f'^'*! for 8 days, CYP activities were assessed using caffeine (CYP1A2), In rats, potential pharmacodynamic interactions have been tolbutamide (CYP2C9), dextromethorphan (CYP2D6) and mid- reported with antihyperlipidaemia and antihypertensive medi- azoiam (hepatic and intestinal CYP3A). E. purpurea root sig- cines, such as atorvastatin, propranolol, hydrochlorothiazide or nificantly reduced oral clearance of caffeine (27%) but not that captopril.''^'^'^"^'"'^ High doses of oral atorvastatin (lOmg/kg)' of tolbutamide and dextromethorphan. The activity of CYP3A have induced kidney damage if used either alone or in combi- at hepatic and intestinal sites was selectively modulated, as nation with high concentrations of garlic (1% in the food), while systemic clearance of midazoiam following intravenous ad- low doses of atorvastatin (2.5 mg/kg) in combination with high ministration was significantly reduced by 34% (p = 0.003), but concentrations of garlic (0.75% in the food) had a minimal oral clearance (following oral administration) was not altered. nephrotoxic potential.''^^' These results are consistent with Furthermore, hepatic and intestinal availability were signi- the antioxidant and nephroprotective properties of garlic.'^"'^ ficantly affected in opposite directions. Whether the interaction Similarly, garlic homogenate 250 mg/kg either alone or with will lead to inhibition or induction depends on the hepatic and propranolol showed a significant increase in the activity of intestinal extraction ratios of the particular CYP3A sub- antioxidant enzymes during ischaemia-reperfusion myocardial strate.''*'^ Two other clinical trials suggested that E. purpurea damage. However, garlic homogenate 500 mg/kg failed to provide (801 mg/day or 1600 mg/day) had no significant effect on the a cardioprotective effect.''^^^ Furthermore, garlic homogenate activities of CYP1A2, CYP2D6, CYP2E1 and CYP3A4.'45.48] 250 mg/kg together with hydrochlorothiazide exhibited syner- Furthermore, Echinacea (267 mg three times daily) did not af- gistic cardioprotective and antihypertensive properties against fect the disposition of digoxin; therefore, P-gp-mediated drug fructose- and isoproterenol-induced toxicities.'''^''^^' Combined interactions are unlikely to occur with Echinacea.^^^^ therapy with garlic (250 mg/kg) and captopril demonstrated In 15 HIV-infected patients, E. purpurea treatment (500 mg even greater synergistic antihypertensive and cardioprotective every 6 hours) for 14 days did not change the overall pharma- effects.''^'^°°^ Indirect clinical evidence implied a potential role cokinetics of darunavir or ritonavir.'^"' Likewise, in 13 healthy of garlic-derived S-allylmercaptocysteine for improving doc- volunteers, the pharmacokinetics of lopinavir or ritonavir were etaxel-based chemotherapy in the treatment of hormone- not significantly altered by co-administration of E. purpurea refractory prostate cancer.'^"-^! Importantly, garlic extracts can (500 mg three times daily) for 14 days.'^^' In contrast, after 28 protect against ciclosporin-induced nephrotoxicity or hyperli- days oí E. purpurea co-administration (500 mg three times daily), pidaemia in rats and renal transplant patients.' the AUC of midazoiam was significantly decreased (p = 0.008) and, consequently, oral clearance was increased (p = 0.02), 2.3.1 In Vitro arid Animal Studies whereas no effect on the pharmacokinetics of fexofenadine was Modulation of the activity and expression of CYPs is de- found, indicating induction of CYP3A but no effect on P-gp.'^^) pendent on the type and chemical composition of garlic sup- Additionally, in 12 healthy subjects, concomitant treatment plements and their dosage regimen.'^''^•^'^^l Two studies with with Echinacea (1275mg four times daily containing 600 mg human liver microsomes demonstrated that extracts of fresh of £•. angustifolia root and 675 mg oí E. purpurea root) shghtly and aged garlic (if stored in an ethanol solution for 20 months) increased oral clearance of S-warfarin but did not have a could inhibit complementary DNA (cDNA)-expression of clinically significant effect on warfarin pharmacodynamics.'^^^ CYP2C9, CYP2C19 and CYP3A, as well as P-gp activity, but Although the potential for Echinacea to inhibit CYPs or P-gp had no effect on CYP2D6.'^°^'2°^] Six water-soluble components needs further investigation, the currently available evidence in- of aged garlic extract failed to produce more than 50% inhibition of dicates that Echinacea does not appear to pose a risk to consumers. CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A even at high concentrations (lOO^imol/L).'^"^! Exposure of 2.3 Garlic human hepatocytes to increasing concentrations of garlic extracts Garlic (Allium sativum) has been generally used for the (0-200 ng/mL) revealed a concentration-dependent reduction in treatment of hypercholesterolaemia, prevention of arterio- CYP2C9 activity and mRNA expression, but no effect on

CYP3A4 activity was seen.^'"' The diallyl disulfide in garlic cancer, co-administration of garlic 600 mg twice daily reduced oil inhibited CYP2A6 activity in a competitive/noncompeti- systemic clearance of docetaxel (a CYP3A4 substrate) to 77% tive mixed manner, with an inhibition constant (Kj) value of and 65% on days 8 and 15, respectively (p = 0.17). However, in 2.13|xmol/L.PH] patients carrying a CYP3A5* 1A alíele, it cannot be excluded that Furthermore, in human K562 leukaemic cells and mouse he- garlic could decrease clearance of docetaxel.'^^^ Garlic extract patocytes, diallyl sulfide (8.75 x 10"^ mol/L) effectively inhibited had no effect on CYP3A4 in human intestine and liver but in- the induced P-gp overexpression.'^'^l However, in human mul- duced intestinal expression of P-gp to 131% (95% CI 105, 163) tidrug-resistant carcinoma KB-C2 cells, diallyl sulfide and diallyl and decreased the saquinavir AUC to 85%.^^^^ In 16 subjects, trisulfide showed no inhibitory effects on P-gp.^'^l This fmding is long-term administration of an aged garlic extract (approxi- consistent with a recent observation that in Caco-2 cells, garlic mately equivalent to six or seven cloves of garlic) for 3 months had no inhibitory potential on P-gp-medi.ated transport of di- had no effect on the pharmacokinetics of paracetamol (aceta- goxin.P''*' Interestingly, hydrophilic sulphur compounds of gar- minophen), a drug partly metabolized by CYP2E1 .'^'1 lic increased P-gp mediated rhodamine 123 (Rhol23) efllux, Because garlic has complex cardiovascular effects, including whereas the lipophilic fraction increased P-gp efflux through the anticoagulant and antiplatelet activity, it could theoretically rat ileum but not through Caco-2 cell monolayers.P'^'-^'^l interact with anticoagulant or antiplatelet drugs.^^^^ One case In rats, garlic oil and its three organosulfur compounds report suggested that garlic can increase the international nor- (diallyl sulfide, diallyl disulflde and diallyl trisulfide) can in- malized ratio (INR) in patients previously stabilized on war- crease the protein content and mRNA levels of CYPlAl, farin.'^^1 However, co-administration of garlic (4g/day) did not CYP2B1 and CYP3Al.P06.2i7] Likewise, diallyl sulfide can in- significantly alter the pharmacokinetics or pharmacodynamics hibit CYP2E1 expression and activity.^'^l of warfarin.f^^'^^l Therefore, garlic extract is relative safe and Some in vitro interactions of ritonavir, saquinavir and dar- poses no serious haemorrhagic risk to patients on monitored unavir with garlic have been demonstrated, but the results have warfarin therapy. Another case report indicated that garlic been contradictory.P'^'^^^l In Caco-2 cells, allicin exhibited con- could decrease the INR in patients receiving the anticoagulant centration-dependent inhibition of ritonavir efflux. In addition, allicin inhibited CYP3A4 activity when tested with the Vivid® Garlic is commonly used by HIV-infected patients to im- CYP3A4 assay kit.P'^1 As saquinavir and darunavir are bound prove health and to treat some opportunistic infections, and it to different binding sites on P-gp and/or multidrug resistance has the potential for interactions.'^^''! In ten healthy subjects, a associated protein (MRP)-2, opposite in vitro interactions were significant decline in plasma concentrations of saquinavir was observed. Aged garlic extracts caused significant inhibition of reported after administration of garlic (~8 g raw garlic/day) for saquinavir efflux from HepG2 cells and rat liver slices, while in over 3 weeks.'6^*1 In contrast, in ten healthy volunteers, dosing of both liver models, the activity of darunavir efflux transporters garlic extract (two 5 mg capsules) taken twice daily over 4 days increased significantly.P^°'-^^'l Moreover, aged garlic extracts did not significantly alter the single-dose pharmacokinetics of can significantly elevate the efflux of saquinavir and daruna- ritonavir.'^-'] As both, saquinavir and ritonavir are substrates of vir from enterocytes into gastrointestinal lumen, whereas their CYP3A4 and P-gp, the reason for the discrepancy is presently CYP3A4 metabolism is inhibited.'^^^' Therefore, garlic can mod- unclear. A longer duration of garlic therapy may be required in ify the hepatic and intestinal transporter-enzyme interplay, order to observe a significant decrease in plasma concentrations possibly leading to pharmacokinetic interactions. of ritonavir. While further information in humans is awaited, caution is 2.3.2 Ciinicai Studies advised if garlic is taken concomitantly with substrates of Three clinical trials in healthy volunteers indicated that garlic CYP2E1, CYP3A4 or P-gp or with antiretroviral drugs (i.e. oil may selectively inhibit CYP2E1 activity, as revealed by de- saquinavir and ritonavir). creased 6-hydroxychlorzoxazone/chlorzoxazone serum ratios. Following administration of a cocktail containing midazolam, 2.4 Gitikgo caffeine, chlorzoxazone and debrisoquine, no effect on the activity of CYP1A2, CYP2D6 or CYP3A4 is likely.'^s-sv] jn 14 Ginkgo {Ginkgo biloba) is among the most popular herbal healthy volunteers, garlic extract (1800 mg twice daily) had medicines worldwide. It is used for the treatment of cerebral no effect on the activity of CYP2D6 (dextromethorphan) and insufflciency or peripheral vascular disease, and is frequently CYP3A4 (alprazolam).'^"'1 In ten women with metastatic breast taken for enhancement of memory function.'^^^^ The flavonol

glycosides (e.g. quercetin, kaempferol and isorhamnetin) and stituents were significant inhibitors of CYPs.'^^"*'-^^^' The mode terpene trilactones (e.g. Ginkgo bilobalides A, B and C; and of inhibition is competitive, noncompetitive or mixed, depen- bilobalide) are the major constituents of Ginkgo. Most studies ding on the enzyme and flavonol tested. Modulation of CYPl Al have been performed using EGb 761, a well defined extract of or CYPlB1 activity or gene expression by GBE was also observed G. biloba. in other in vitro studies.'^^^-^^^ G. biloba has clinically relevant antipiatelet activity, and Recently, in cultured primary human hepatocytes, the effects many detailed reports of haemorrhage (usually cerebral, ocular of GBE (2.19-219 ng/mL) on CYPs were evaluated."85-i88] or postsurgical) in patients using G. biloba extracts (GBE) have GBE may exert opposite and biphasic effects on CYP1A2 and been published.'^^*1 Co-administration of G. biloba (120 mg) CYP2D6 metaboHsm. Induction of CYPl A2 and inhibition of with either ciiostazol or clopidogrel did not enhance anti- CYP2D6 were found at low concentrations (2.19(ig/mL); the platelet activity but did potentiate the prolongation of bleeding opposite was observed at higher concentrations (219 |ig/mL).''^^ time induced by ciiostazol.'^"' In contrast, studies using in vitro Likewise, GBE (2.19-219 |xg/mL) showed an induction/inhibi- and in vivo models have reported that G. biloba may potentiate tion profile towards CYP2C19 but a weak inhibitory effect on the antiplateiet effect of ciiostazol without prolongation of CYP2El.''«^i It was also able to inhibit CYP2D6 or CYP3A4 bleeding time or coagulation time.'^^'' Recently, in elderly activity, but P-gp activity was unaffected.''^^''^^' In Caco-2 patients with peripheral artery disease, EGb 761 (300 mg/day) monolayers, the Ginkgo flavonols quercetin, kaempferol and combined with aspirin (325 mg/day) did not have a significant isorhamnetin were substrates of P-gp and appeared to inhibit or impact on coagulation examined over 4 weeks.'^^^l This result is induce P-gp activity.'^^^' consistent with findings where co-administration of ace- Likewise, in rats, GBE can induce or inhibit various CYPs, tylsalicylic acid and EGb 761 did not constitute a safety risk.'^^^' depending on the compositions or constituents of the GBE.'^^^"^''^' Likewise, a clinical review indicated that Ginkgo did not sig- In rats that were fed a diet of 0.5% GBE over 5 days, CYPlAl, nificantly affect the safety of co-administered aspirin (acet- CYP1A2, CYP2B, CYP2C, CYP2E1, CYP3A4 and glu- ylsalicylic acid) or tathione S-transferase (GST) were induced in the liver.'^'"''^'*'' The inductive effect was rapidly reversible after discontinuation of GBE even after excess treatment.'-^^'^ However, addition of 2.4.11n Vitro and Animai Studies GBE to rat and human hepatic microsomes can cause con- Several studies have indicated that various constituents of centration-dependent inhibition of various CYP activities. Be- G. biloba have different effects on CYPs. One study with human liver cause of inductive effects on CYP2C, CYP2B and CYP3A, microsomes indicated that GBE is a potent inhibitor of CYP1A2, pretreatment with a 0.1% GBE diet in rats significantly affected CYP2C19 and CYP2C19 but did not inhibit CYP2D6 and the hypoglycaemic action of tolbutamide (CYP2C)'^''^' and re- CYP3A4.'2O»1 The flavonoidic fraction of EGb 761 showed duced the therapeutic potency of phénobarbital (CYP2B) and strong inhibition of CYPl A2, CYP2E1, CYP2C9 and CYP3A4, nicardipine (CYP3A4).'^'*'*"^'*^ In contrast, co-medication with whereas the terpenoidic fraction inhibited only CYP2C9. The GBE (20 mg/kg) did not affect the pharmacokinetics after in- majority of EGb 761 fractions can inhibit CYPs at low levels travenous administration of the CYP3A4 substrates nifedipine (concentration of drug producing 50% inhibition [IC50] (2.5 mg/kg) or ciclosporin but markedly increased the absolute <40ng/mL).'^^'' In human and rat priniary hepatocytes, GBE bioavailability after oral administration, suggesting that GBE (100-2500 ng/mL) significantly induced the activity, protein inhibited intestinal CYP3A4 without affecting hepatic CYP3- expression and mRNA expression of CYP3A in a dose-depen- ^4 [247,248] jjj addition, GBE (10 or lOOmg/kg/day) can decrease dent manner.'232] Similarly, GBE had minor effects on CYP2D6 the oral bioavailability of propranolol (10 mg/kg) and theophyl- and caused moderate inhibition of CYP2C9, as well as mild-to- line (10 mg/kg) [CYP1A2] because of enzyme induction.'249.250] moderate inhibition of CYP3A4, depending on the substrate that was used."^'" In addition, Ginkgo can inhibit CYP2C8 at 10 |imol/L but has no effect on P-gp.'^^^' 2.4.2 Ciinicai Studies Interestingly, two separate in vitro studies indicated that ter- The effect of GBE on various CYP isoforms has been widely pene trilactones and flavonol glycosides of GBE did not sig- investigated in clinical studies using different probes, such as caffeine nificantly inhibit the activities of CYPlAl, CYP1A2, CYPIBI, (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), diclo- CYP2C9 and CYP3A4. However, flavonol aglycones, the bi- fenac (CYP2C9), flurbiprofen (CYP2C9), diazepam (CYP3A4 flavonol amentoflavone and several other non-glycosidic con- and CYP2C19), debrisoquine (CYP2D6), dextromethorphan

(CYP2D6), chiorzoxazone (CYP2E1), alprazolam (CYP3A4) 2.5 Goldenseal or midazoiam (CYP3A4).[55,56,68,69,7i,72,75,77,79] jjj j^Q3^ studies, GBE had no significant effect on CYP1A2, CYP2D6, CYP2E1, Goldenseal (Hydrastis canadensis) is one of the most popular CYP3A4, CYP2C9, CYP2C19 or CYP2B6.'^5,56,68,69,71,72,77] herbs used as a topical antimicrobial. It is especially useful for In ten healthy volunteers, GBE (360 mg/day) slightly but digestive disorders because of its alterative, anticatarrhal, anti- significantly decreased the AUC of tolbutamide by 16%. The infiammatory, antimicrobial, laxative, emmenagogue and oxy- AUC of midazoiam was significantly increased (by 25%) and tocic properties.'^^'' Goldenseal contains various isoquinoline oral clearance was decreased (by 26%).[^'l In contrast, in one alkaloids: hydrastine, berberine, berberastine, hydrastinine, tetra- clinical trial, GBE (120 mg twice daily for 28 days) decreased the hydroberberastine, canadine and canalidine, of which hydrastine AUC and C^^ of midazoiam by 34% (p=0.03) and 31 % (p=0.03), and berberine are the main active constituents.'^^^' respectively, suggesting that GBE could induce CYP3A.t''^' O'ral ingestion of GBE (240 mg) did not significantly affect the 2.5.1 In Vitro and Animal Studies pharmacokinetics of nifedipine, another CYP3A4 substrate. Six studies have assessed the impact of goldenseal on CYP Hôwever, in two subjects, the Câx of nifedipine was approxi- isoenzymes."*3''^^'233'253-255] /„ y^^.^ goldenseal inhibited CYP2C8, mately doubled. In addition, both subjects had more severe and CYP2C9, CYP2C19, CYP2D6 and CYP3A4.'i«3,233,253,254] B^^J^ longer-lasting headaches, dizziness or hot fiushes, and a trend upregulation and downregulation of CYP3A4 expression were towards higher heart rates when GBE was co-administrated.[^°' observed with varying concentrations of goldenseal. It appeared GBE (90 mg/day for 30 days) did not have a major impact on to have no effect on P-gp.[233,255] jjj addition, goldenseal is a strong the pharmacokinetics and pharmacodynamics of donepezil, a inhibitor of CYP2E1, and the inhibition appeared to be related substrate of CYP2D6 and CYP3A4.'''''] EGb 761 (120 mg/day to the presence of the alkaloids berberine, hydrastine and cana- for 90 days) did not significantly affect the pharmacokinetic dine in the extract. These compounds inhibited CYP2E1, with properties of metformin.'^^l K, values ranging from 2.8 |xmol/L for hydrastine to 18 ^mol/L Two separate studies in healthy Chinese subjects examined for berberine.f'^'i In contrast, in rats, berberine (30 and 100 mg/kg) whether the effect of GBE on CYP2C19 activity was modulated by produced a dose-dependent increase in the bioavailability of di- the CYP2C19 metabolizer status.'^''^^ Twelve days of treatment goxin and ciclosporin by inhibition of intestinal P-gp, but no sig- with GBE (120mg twice daily) did not significantly alter the nificant effect of berberine on CYP3A activity was observed.'^^^^ pharmacokinetics of voriconazole in either extensive or poor metabolizers of CYP2C19.'*'^ In contrast, 12 days of treatment with 2.5.2 Clinical Studies GBE (140mg twice daily) induced hydroxylation of omepra- Three studies conducted in healthy volunteers evaluated the zole in a CYP2C19 genotype-dependent manner. Concurrently, impact of goldenseal on the activities of CYP3A4/5, CYP1A2, renal clearance of 5-hydroxyomeprazole was reduced.'^'l Re- CYP2E1 and CYP2D6 by using midazoiam, caffeine, chiorzo- sults from some clinical trials in healthy subjects indicated that xazone and debrisoqtiine, respectively.''*^-''^'^^! Goldenseal strongly GBE did not significantly affect the pharmacokinetics or inhibited CYP2D6 and CYP3A4/5 activity, whereas no effect on pharmacodynamics of warfarin or ticlopidine.'^'*"^^'^^' CYP2E1 and CYPl A2 activity was noted. However, in ten healthy The effects of GBE on the pharmacokinetics of the P-gp subjects, goldenseal root (1140 mg twice daily) did not signi- substrates digoxin, talinolol and fexofenadine have been exam- ficantly inñuence the pharmacokinetics of the CYP3A4 sub- ined in healthy volunteers.'"'''^'''^'^2,83] Qgg (120 mg twice daily strate indinavir.'^^l In 12 healthy volunteers, goldenseal (3210 mg for 28 days or 80 mg three times daily for 7 days) did not have any daily) increased the Câx of digoxin by only 14%, indicating no significant effect on the disposition of digoxin, fexofenadine or impact on P-gp activity.'^'! lopinavir (a CYP3A4 and P-gp substrate).'^^'^^! However, long- Berberine markedly increased blood concentrations of ciclo- term use of GBE (360 mg/day for 14 days) significantly in- sporin in healthy volunteers given a dose of 0.3 g and in renal creased the Câx and AUC of talinolol, probably by inhibition transplant recipients given 0.2 g three times daily for 12 days,'^'-'"' of P-gp-mediated drug efflux.t^^-^^l Likewise, in 12 healthy which could be explained by inhibition of CYP3A4 in the liver subjects, short-term use of quercetin (500 mg/day for 7 days) and/or small intestine. increased plasma concentrations of fexofenadine.'^^1 Overall, the available clinical evidence suggests that berbe- In summary, consumption of GBE should be monitored in rine from goldenseal has the potential to interact with CYP3A4 patients receiving drugs metabolized by CYP2C19, while the substrates. Goldenseal does not notably modify P-gp; therefore elïect of GBE on CYP3A4 or P-gp requires additional study. an interaction with digoxin is very unlikely.

2.6 Kava and CYP2C19 activities by methysticin, dihydromethysticin and desmethoxyyangonin ranged from 5 to 10|imol/L.'^™^ Therefore, Because of its anxiolytic and sedative properties, kava (Piper kava has a high potential for causing pharmacokinetic interactions methysticum) is a popular herbal medicine used in the treatment at the site of drug metabolism. of anxiety, depression, insomnia and restlessness.'^^'' The active ingredients in kava root are known as kavalactones, including 2.6.2 Clinical Studies kawain, dihydrokawain, methysticin, dihydromethysticin, yan- Four studies evaluated the effect of kava (2000, 408.9 or gonin and desmethoxyyangonin. Recently, concern about the 3681 mg/day) on CYP isoenzymes.''^-''^-^-'-^''^ Kava could signif- hepatotoxicity of kava has been raised'^^^' and, for this reason, icantly inhibit CYP2E1 activity but had no impact on the activities the herb has been withdrawn from European markets.'^^^^ of CYP3A4/5, CYP1A2 or CYP2D6.'^-45-53] Only one study has Additionally, the FDA has issued a safety alert about kava and shown that kava may inhibit CYP1A2 activity, but no effects on its liver problems.'^^'^l Potential pharmacodynamic interactions CYP2C19, CYP3A4, CYP2D6 and CYP2E1 were found.'^^'l with alprazolam and levodopa have been also reported.' Twenty healthy volunteers received a standardized kava supplement (1227 mg daily) for 14 days. No significant effects on the disposition of digoxin were observed,'''^ suggesting that 2.6.1 In Vitro and Animal Studies kava did not modulate the function of P-gp. The impact of kava extracts and individual kavalactones on In conclusion, caution is advised if kava is taken concomitantly CYP enzymes has been investigated, using human liver micro- with CYP2E1 substrates. There is no evidence that kava affects somes.'^^^l Whole kava extract significantly reduced the activity substrates of CYP2C19, CYP3A4, CYP2D6 and P-gp, but fur- of CYP1A2 (56% inhibition), CYP2C9 (92%), CYP2C19 (86%), ther investigations are necessary to strengthen this impression. CYP2D6 (73%), CYP3A4 (78%) and CYP4A9/11 (65%), whereas no effect on CYP2A6, CYP2C8 and CYP2E1 was found. Except for kawain, the major kavalactones (including desmethoxyyan- 2.7 Milk Thistle gonin, methysticin and dihydromethysticin) can inhibit CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Similarly, in both cDNA- Milk thistle (Silybum marianum) is one of the most commonly expressed human enzymes and cryopreserved human hepatocytes, used herbal medicines for treatment of alcoholic liver disease, the kava extract and three kavalactones (methysticin, desmeth- acute and chronic viral hepatitis, and toxin-induced liver diseases. oxyyangonin and yangonin) were found to be potent inhibitors of Its major active constituent is a lipophilic extract from seeds, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and it is composed of three isomer flavonoHgnans (silybin, sily- CYP4A9 and CYP4A11.'208-263-265] j^ava also caused a dose- dianin and silychristin), collectively known as silymarin. Silybin dependent decrease in the activity of CYP3A4, with an IC50 value is the component with the most pronounced biological activity of 15.5^g/mL,'^^^ and was capable of inducing CYP3A4 via and makes up 50-70% of silymarin.'2''2] human PXR.'2^öl Additionally, an in vitro assessment of kava Aqueous extracts of milk thistle exhibited potent hypogly- extracts and kavalactones demonstrated that they inhibited P-gp caemic and anti-hyperglycaemic activities in normal and strep- activity, with concentrations needed to double baseline fluores- tozotocin-induced diabetic rats.'^'^^ In type II diabetic patients, cence values of 170 |J.g/mL and 17-90 fimol/L, respectively.'^*^ potential pharmacodynamic interactions may exist, related to In rats, kava extract and kavalactones had some impact on the ability of milk thistle to reduce blood sugar levels.'^^'*' Thus CYP isoenzymes.'^^^'^'O' The kava alkaloid piper methystine was milk thistle should be used with caution in patients receiving capable of inducing CYPl A2 and CYP2E1 .'26«] A, high dose for hypoglycaemic agents. In 59 patients with beta-thalassaemia 8 days (equivalent to approximately 380 mg of kavalactones/ major treated with desferrioxamine, combined therapy with sily- kg/day; 100 times the suggested dosage for human use) of two marin (140mg three times daily) was more effective than desfer- different types of kava products significantly increased the liver rioxamine alone in reducing serum ferritin levels. Significant weight, CYPl A2 mRNA expression (2.8- to 7.3-fold) and CYPlAl improvements in liver alkaline phosphatase and glutathione le- mRNA expression (75- to 220-fold).'2*^^' In rats, a 7-day pretreat- vels in red blood cells were also observed.'"' ment with kava extract (256 mg/kg/day) only modestly induced hepatic CYP activity. However, in microsomes, kava can inhibit 2.7.1 in Vitro and Animai Studies CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activity in a concen- In vitro studies have indicated that both silymarin and sily- tration-dependent manner. Kj values for the inhibition of CYP2C9 bin can inhibit various CYP isoenzymes (e.g. CYP2D6, CYP2E1, ffl 2012 Adis Data intormation BV, Ali rights reserved. Ciin Pharmacokinet 2012; 51 (2) Ding Interactions with Herbal Medicines 91

CYP3A4, CYP2C9 or CYP2C8) and uridine diphosphate cancer patients, short-term (4 days) or prolonged intake of milk glucuronosyltransferase (UGT).'2".255,275-279] silymarin and thistle 200 mg three times daily for 12 days did not infiuence silybin inhibited CYP2D6, CYP2E1 and CYP3A4 actiyity in a the pharmacokinetic properties of irinotecan (a substrate of dose-dependent manner.'^^^-^^^^ Silybin inactivated purified, CYP3A4 and UGT1A1).P8' Additionally, in 16 healthy male recombinant CYP3A4 and CYP2C9 in a mechanism-based volunteers, co-administration of silymarin (280 mg adminis- manner and inhibited the glucuronidation of 7-hydroxy-4-trifluo- tered 10 hours and 1.5 hours prior to the administration of romethylcoumarin catalysed by recombinant hepatic UGTIAI, nifedipine) did not change the absorption or the metabolism of 1A6, 1A9, 2B7 and 2B15, with IC50 values of 1.4, 28, 20, 92 and the CYP3A4 substrate nifedipine.''^'l However, in 12 healthy 75 nmol/L, respectively.'^^^' However, in one study, silybin and its subjects, administration of silymarin (140 mg/day for 9 days) synthetic beta-glycosides showed no interference with mRNAs increased clearance of metronidazole (a substrate of CYP3A4 and expression of CYPl A2 and CYP3A4.'28O] and CYP2C9) and that of its major metabohte by 30% and Only at the high concentration of 100|xmol/L of silymarin 32%, respectively, with a concomitant decrease in the ti^, Cmax has more than 50% inhibition of CYP2B6, CYP2C8, CYP2C9, and AUC, indicating induction of both intestinal P-gp and CYP2C19, CYP2D6, and CYP3A4 been observed, and no inhibition or moderate inhibition was found for CYPl A2, CYP2A6 In 12 healthy men of known CYP2C9 genotype (six and CYP2El.[^^'i In a follow-up study with dry extract from CYP2C9*\r\ and six CYP2C9*\n), the effects of silymarin milk thistle, no inhibition or minor inhibition was noted for all (420 mg/day for 14 days) on the pharmacokinetics of losartan CYPs tested at the lowest extract concentration of 1.5pg/mL. and its active metabolite E-3174 were investigated. Silymarin sig- At concentrations of 15 and 150 [xg/mL, the extract significantly nificantly decreased the AUC of E-3174 in both CYP2C9*\n inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP2C9*\r7> subjects and significantly increased the AUC and CYP3A4.'^^^' However, in view of the clinically relevant of losartan. The metabolic ratio of losartan was decreased in plasma concentration being substantially lower than the inhi- individuals with the CYP2C9*\r\ genotype but not in those with bitory concentrations estimated in these studies, it is unlikely that the CYP2C9*\ri> genotype. Thus silymarin inhibited the me- there will be an interaction problem with silymarin. Using a tabolism of losartan to E-3174, and the magnitude of the inter- baculovirus expression system or Caco-2 cells, three studies indi- action was dependent on the CYP2C9 genotype.''^' In eight cated that milk thistle had no effect on P-gp activity.'2'''233.255] healthy male volunteers, silymarin (140mg three times daily for In rats, the pharmacokinetic interaction between silymarin 5 days) did not affect the pharmacokinetics of rosuvastatin, sug- (single doses of 50 and 100 mg/kg for intravenous and oral ad- gesting that silymarin is not a potent modulator of OATPIBI or ministration, respectively, and oral administration of 100 mg/kg • breast cancer resistance protein.''^-'^ for 14 days) and oltipraz was investigated.'^^'-'^ After single Other studies have demonstrated that milk thistle did not intravenous administration of both drugs together, the AUC of alter the pharmacokinetics of indinavir'^^''^^ or ranitidine,''"^' unconjugated silibinin was significantly decreased (33%), but indicating no significant effect on CYP3A4 and P-gp activity. those of conjugated and total silibinin were significantly increased Likewise, in 16 healthy subjects, milk thistle (900 mg daily for (32% and 27%, respectively). However, after simultaneous oral 14 days) had no effect on the disposition of digoxin.'''^' In 18 administration of the drugs, the AUCs of unconjugated, conju- healthy adult men of known MDRl genotype, the effect of sily- gated and total silibinin were comparable. Silymarin did not marin (140 mg three times daily for 14 days) on the phar- significantly alter the pharmacokinetic parameters of oltipraz. macokinetics of the P-gp substrate talinolol and its association Likewise, in rats, no marked effects of silymarin (0.5 g/kg) and with MDRl C3435T genetic polymorphism were investigated.''"^! silibinin (0.175 and 0.35 g/kg) on the pharmacokinetics of trazo- Silymarin significantly increased the C^ax of talinolol (p = 0.007), done have been observed with normal daily the AUC from 0 to 36 hours by 36% and the AUC from 0 hours to infinity by 37%, and decreased oral clearance by 23% (p< 0.001). These effects were independent of the MDR genotype. 2.7.2 Clinical Studies In summary, findings in humans have been contradictory, In healthy volunteers, the impact of milk thistle on CYP iso- and further studies are needed to elucidate the role of milk forms was investigated using caffeine, debrisoquine, chiorzoxazone, thistle in altering drug disposition by affecting CYP1A2, midazoiam or nifedipine.''*^''*^''*^-'°'l Contrary to previous CYP2D6, CYP2E1 or CYP3A4 or P-gp. Milk thistle does not in vitro studies, milk thistle supplement had no significant effect affect P-gp in humans, which is consistent with findings from on CYP1A2, CYP2D6, CYP2E1 or CYP3A4. Likewise, in six laboratory studies.

2.8 Panax ginseng Recently, the inhibitory effects of 15 ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 Panax ginseng (Asian ginseng) has been used in Eastern Asia for and CYP3A4 enzymes were evaluated by using commercially more than 2000 years. Ginseng, the root of P. ginseng, has diverse available fluorescent probes.t^'"*! Ginsenosides Rg3 and C-K pharmacological activities, including effects on the central nervous had moderate inhibitory effects on CYP1A2, while ginseno- system, antineoplastic effects and immuhomodulatory effects. Its sides Rg3, Rh2 and C-K and all sapogenins exhibited moderate major active components are ginsenosides, a group of steroidal sa- inhibition on CYP2C19 and more potent inhibition of CYP2C9 ponins, which may be responsible for ginseng-drug interactions.P^^ and CYP3A4. Ginsenoside Rbl, Re and Rgl had no significant Potential pharmacodynamic interactions of P. ginseng with effects on the activity of flve CYPs, with the exception that Rbl antiplatelet/anticoagulant drugs have been reported.!^^^! P. gin- moderately inhibited CYP1A2. seng has been shown to decrease the effect of In rats, P. ginseng extracts (4% [w/w] total ginsenosides; 30 or However, three clinical trials could not confirm these results.t 100 mg/kg/day for 1 or 4 days) did not increase hepatic CYP2B1, Recently, in a patient with chronic myelogenous leukaemia, im- CYP3A23 or CYP1A2 gene expression.!^^^] in addition, atinib-induced hepatotoxicity after concurrent ginseng ingestion P. ginseng (150 mg/kg/day) for 14 days decreased the AUC from was reported.!^^^! It was proposed that the patient's late onset 0 to 12 hours of oral fexofenadine by 51% (p < 0.005), decreased of imatinib-associated hepatotoxicity was due to an interaction the Cmax by 75% (p < 0.001) and significantly reduced the ratios between ginseng and imatinib through CYP3A4. of brain to plasma concentrations (p<0.05). Therefore, long- term administration of P. ginseng might induce the expression 2.8.11n Vitro and Animal Studies of both intestinal and brain endothelium P-g Several in vitro studies have evaluated the effects of ginseng or its extract constituents on CYP isoforms.P'9.289] Ginseng can 2.8.2 Clinical Studies inhibit CYP2C9, CYP2C19, CYP2D6 and CYP3A4.P89] Purified In healthy volunteers, P. ginseng (1500 mg/day) had no effect kaempferol from ginseng has exhibited remarkable inhibition of on CYP3A4, CYPl A2, CYP2E1 and CYP2D6 when midazolam, P-gp-mediated efflux of ritonavir and CYP3A4 activity.!^'^! caffeine, chlorzoxazone and debrisoquine were used.!^^'^^! Unfortunately, the reported effects of ginseng extracts or In the elderly (mean age 67 years), P. ginseng weakly in- ginsenosides on CYPs have been inconsistent and even con- hibited CYP2D6 activity, but the magnitude of the effect (ap- flicting.f^'^"^^^! The effects of seven ginsenosides and two eleu- proximately 7%) did not appear to be clinically relevant.t^^' In therosides on the catalytic activity of cDNA-expressed CYP addition, P. ginseng increased plasma concentrations of nifedi- isoforms have been investigated.!^^**! Ginsenoside Rd weakly in- pine at 0.5 hours; however, data on additional time points were hibited CYP3A4 and inhibited CYP2D6, CYP2C19 and CYP2C9 not provided.t'"^! So far, no clinical studies have been carried out to an even lesser extent, while ginsenoside Re and Rf increased to assess the impact of ginseng on P-gp. Therefore, the available CYP2C9 and CYP3A4 activity. Ginsenosides Rbl, Rb2, Re clinical evidence suggests that the potential for ginseng-drug and Rgl did not significantly affect CYP1A2, CYP2C9, interactions is low. CYP2C19, CYP2D6 and CYP3A4 activity.P^o] However, in another study, ginsenosides Rd and Rb2 inhibited CYP2C19 2.9 Panax quinquefolius and CYP2D6 activity. For CYP2C19, the IC50 values were 46 and 62|xmol/L for ginsenoside Rd and ginsenoside Rb2, re- Panax quinquefolius (American ginseng) has been reported to spectively, whereas only ginsenoside Rd had an IC50 value of have a wide range of pharmacological effects on the cardio- 57 ^mol/L for CYP2D6.I2911 Additionally, standardized P. gin- vascular and central nervous systems, antidiabetes effects, anti- seng extract decreased the 7-ethoxyresorufm 0-dealkylation tumour activities and immunomodulatory effects similar to those activities of human CYPlAl, CYP1A2 and CYP'lBl, but gin- of P. ginseng.^'^^^^ Ginsenosides are also its major biologically senosides Rbl, Rb2, Re, Rd, Re, Rf and Rgl had no significant active constituents. Chemically, severaL differences exist be- effects.t^^^! Interestingly, the naturally occurring ginsenosides tween P. quinquefolius and P. ginseng. An important parameter exhibited no inhibition or only weak inhibition of human used for the differentiation is the presence of ginsenoside Rf CYP3A4, CYP2D6, CYP2C9, CYP2A6 and CYP1A2 activ- in P. ginseng versus the presence of pseudoginsenoside Fll in ities, but their main intestinal metabolites (compound K [C-K], P. quinquefolius.^-^^^'-^^^^ protopanaxadiol and protopanaxatriol) demonstrated a wide Compared with the long history of use and the widespread range of inhibition of CYP-mediated drug research on P. ginseng, the data on P. quinquefolius are relative

limited. In 32 healthy young adults, enhancement of the robust 2.10.2 Ciinicai Studies working memory has been observed following administration Results in humans have been inconsistent with data from clin- of three doses (100, 200 or 400 mg) oí P. quinquefoHus.^^^'^^ These ical studies. In 12 healthy volunteers, saw palmetto (320 mg/day for effects are distinct from those of P. ginseng and suggest that the 28 days) had no significant effect on CYPl A2, CYP2D6, CYP2E1 psychopharmacological properties depend critically on the gin- and CYP3A4 activity when caffeine, debrisoquine, chlorzoxazone senoside profiles. Another clinical trial conducted in 20 healthy and midazolam were used,''*^' Use of saw palmetto (320 mg/day patients found that P. quinquefoHus reduced the anticoagulant for 14 days) had similar effects on the activities of CYP2D6 or effect of warfarin after 2 weeks of ginseng administration.'""' CYP3A4 when the probes dextromethorphan and alprazolam were used.'"^' Therefore, botanical supplements containing saw 2.9.1 Animal Studies palmetto extracts appear to pose a minimal risk of CYP-mediated In rats, P. quinquefoHus extracts (10% [w/w] total ginsenosides; interactions. 100 or 400 mg/kg/day for 21 days) did not affect body weight gain; absolute or relative liver weight; hepatic mRNA expression of 2.11 St John's Wort CYP2B1, CYP3A23, or CYPl A2; microsomal CYP2B-mediated 7-benzyloxyresorufin 0-dealkylation; or CYPlA-mediated 7-eth- St John's wort (SJW; Hypericum perforatum), one of the oldest oxyresorufin O-dealkylation.'^'^' and best investigated herbal medicines, is the most commonly used herbal antidepressant for treatment of mild to moderate 2.9.2 Clinical Studies depression,[^''^•^"^1 SJW contains numerous pharmacologically In 13 healthy volunteers receiving indinavir 800 mg every active compounds, including naphthodianthrones (e.g. hyper- 8 hours for 3 days and then indinavir and P. quinquefoHus 1 g every icin and pseudohypericin), phloroglucinols (e.g. hyperforin and 8 hours for 14 days, the potential interactions between both adhyperforin) and fiavonoids (e.g. quercetin, quercitrin and 13, agents was tested,''"^' Indinavir can decrease insulin sensitivity, 118-biapigenin).'^'''*' Given the widespread use of SJW, a major which was unaltered by P. quinquefoHus co-administration. safety concern is its ability to alter the pharmacokinetics and/ P. quinquefoHus did not significantly affect the pharmacokinetics or clinical response of a variety of clinically important drugs. of indinavir. Another study in ten healthy volunteers showed Several comprehensive reviews have already focused on SJW- that intake oí P. quinquefoHus 200 mg twice daily for 2 weeks did drug interactions.'-'"^"-'^'' not alter the pharmacokinetics of zidovudine but did reduce Potential pharmacodynamic interactions resulting in serotonin oxidative stress markers.'"'^ In summary, the available clinical syndrome can occur when SJW is used with other serotonergic evidence suggests that the potential for P. quinquefolius-drug in- drugs, as a result of additive serotonin effects or inhibition of teractions is low. drug metabolism.f"'''^^'-""' An interaction has been observed between SJW (300 mg twice daily for 4 weeks) and atorvastatin 2,10 Saw Palmetto in patients with hypercholesterolaemia.'"^' SJW can significantly increase the serum levels of low-density lipoprotein Saw palmetto {Serenoa repens) is one of the most widely used and total cholesterol, suggesting a need to increase the dose herbal preparations for the treatment of lower urinary tract of atorvastatin when co-administration of SJW is necessary. In sj'mptoms and benign prostatic hyperplasia.'^*'"' Eatty acids addition, SJW (300 mg three times daily for 14 days) enhanced and sterols are two active fractions of saw palmetto. A recent the antiplatelet effect of clopidogrel in hyporesponsive volun- review suggested that adverse events associated with the use of teers and patients.'^"' saw palmetto are mild, and no evidence for drug interactions with saw palmetto have been reported,'^°'^ 2.11.1 In Vitro and Animal Studies In vitro studies have suggested that SJW extracts can inhibit 2.10.1 In Vitro and Laboratory Studies CYP3A4, CYP2C9, CYP1A2, CYP2D6, CYP2C19 and One in vitro study indicated that saw palmetto showed potent CYP IB I.'24.'83.208,312,313] Importantly, individual constituents inhibition of the activities of CYP3A4, CYP2D6 and CYP2C9,''^'*1 of SJW have different inhibitory effects on CYP isoenzymes. suggesting the potential for drug interactions. Therefore, patients Hyperforin is a potent, noncompetitive inhibitor of CYP2D6 should be encouraged to inform their physicians when using this (K¡ value 1.5nmol/L) and a competitive inhibitor of CYP2C9 herb, and physicians should advise patients of potential risks if and CYP3A4 (K; values 1.8 and 0.48 nmol/L, respectively). herbal medicines are combined with prescription medications. 13,118-biapigenin is a potent, competitive inhibitor of CYP3A4,

CYP2C9 and CYPl A2 (K; values 0.038, 0.32 and 0. its constituents (hyperforin, hypericin and quercetin) on the respectively), and hypericin is a potent inhibitor of several CYP blood-brain barrier function of P-gp were studied.'^^'' SJW extract activities.'^"*' Seven flavonoids (myricetin, apigenin, kaempferol, (0.1-5 |ig/mL) and its constituents hyperforin (0.1-10 îmol/L), quercetin, amentoflayone, quercitrin and rutin) are slightly hypericin (1-50 |xmol/L) and quercetin (l-50ixmol/L) decreased more selective for CYPIBI inhibition (K; value 0.06-5.96 |imol/L) P-gp activity in a dose- and time-dependent manner. SJW and than for CYPlAl inhibition (K; value 0.20-1.6 îmol/L), where- hyperforin directly inhibited P-gp activity, whereas hypericin and as rutin has no inhibitory effect on CYPlAl. Apigenin and amen- quercetin modulated the transporter function through a mechan- toflavone are competitive inhibitors of CYPIBI, while quercetin ism involving protein kinase C. At high concentrations (10 îmol/L), shows mixed-type inhibition.'^'-'' quercetin decreased P-gp activity, but at low concentrations However, most in vitro studies have demonstrated that SJW (l-lOîmol/L), it increased its function. extracts can result in significant induction of CYP3A4.''^^'^''*"^'^' The magnitude of CYP3A4 induction correlated significantly 2.11.2 Ciinicai Studies with the content of hyperforin in the SJW extracts but not with The effects of SJW on CYP isoenzymes have been widely the content of flavonoids or hypericin.'^'''•^'^' Induction of evaluated using probes such as midazolam, alprazolam, nifedi- CYP3A4 by hyperforin is mediated by PXR.'^''*-^'^' In contrast, pine and erythromycin for CYP3A4, tolbutamide for CYP2C9, in human hepatocytes, acute administration of hyperforin at 5 caffeine for CYP1A2, dextromethorphan and debrisoquine for and 10 (imol/L 1 hour before and together with probe substrates CYP2D6, chlorzoxazone for CYP2E1 and omeprazole for inhibited CYP3A4 activity.'^'5' Additionally, SJW showed dose- CYP2C19.'''5.55,56,l 15,120-122,125,129,130,146,148,152,153] SJYV? (900 mg/day dependent induction/inhibition effects against CYP2C19 and for 14 days) significantly induced the activity of CYP3A4, CYP2E1 CYP2E1, with induction at low doses (8 ng/mL) and inhibition and CYP2C19, whereas no effects on CYP2C9, CYP1A2 or at higher doses (800 ^g/mL)."^"" CYP2D6 were observed. CYP1A2 appeared to be induced by Likewise, studies in mice indicated that both CYP3A and SJW only in females.''^°' Importantly, there is considerably less CYP2E1 activities are increased 2-fold by SJW (140 or 280 mg/ induction of CYP3A after intravenous administration of the kg/day) but only following 3 weeks of administration.'^'^' Four probes than after oral administration, suggesting that the pri- days of treatment with moderate to high doses of SJW (435 mg/ mary site of action of SJW is intestinal rather than hepat- kg/day), hyperforin (1 mg/kg/day) or hypericin (10 mg/kg/day) ¿(, [121,125,130] Oral clearance of midazolam was signiflcantly failed to induce the activities of CYPl A2, CYP2E1 and CYP3- increased after administration of St John's wort (300 mg three ^ [320] jj^ mice, hyperforin also played a key role in the induction times daily for 14 days), and CYP3A-induced activity pro- of CYP3A.'^^'' In rats, pharmacokinetic interactions between gressively returned to basal levels approximately 1 week after SJW (150 or 300 mg/day for 15 days) and indinavir have been completion of SJW treatment.'"*^' observed and were due to CYP3A4 induction.'^^^' SJW adminis- Likewise, a few clinical trials have demonstrated an inductive tration (100 mg/kg/day for 10 days) in rats resulted in significant effect of SJW on P-gp. Plasma concentrations and AUCs of induction of CYP2D2 and CYP3A2 and signiflcant inhibition of well known P-gp substrates (including digoxin,'^'•'^°"'^^' fexofe- CYP2C6.'323] Administration of SJW extract to rats for 14 days nadine''25.133,134] and talinolol''^^]) jjave been reduced by SJW. increased intestinal P-gp/MDRl expression 3.8-fold and hepatic Hyperforin, but not hypericin, appears to be the key activator of expression of CYP3A2 2.5-fold."3°' In rats, SJW (400 mg/kg/day PXR, resulting in induction of CYP3A4, P-gp and several other for 10 days) also led to overexpression of hepatic MRP2, GST-P enzymes.''^^'^*®'^'^'^^^' Consistent with in vitro and animals findings, and CYP1A2.'324] Interestingly, SJW (100 and 1000 mg/kg/day) SJW extracts with a low hyperforin content have not demonstrated signiflcantly decreased transcripts of MDRla, MDRlb, MRPl, any clinically relevant interactions."'3''26.i46,i47,i54,305,309,333] MRP2 and CYP3A2 genes in the livers of fetuses and increased Furthermore, short-term (1-3 days) administration of SJW did hepatic levels in the mothers.'^^^' not induce CYP3A4 or P-gp, and longer treatment is generally Several in vitro studies have shown that only long-term ad- required to show the inductive effect.""''"5.i2i,i25,i33,i68,i69] ministration of SJW and hyperforin strongly induces p.gp^[326-330] Interestingly, induction of CYP3A and P-gp activity by SJW and no acute effects on P-gp activity have been observed.'-'^'' (300 mg three times daily for 10 days) was comparable in healthy Induction of P-gp by SJW can be mainly attributed to hyperforin, volunteers from six ethnic populations - namely, Caucasians, but other constituents (e.g. hypericin or quercetin) may also have African Americans, Hispanics, Chinese, Indians and Malays."^**' some inductory effect.'^^^'^^*'^^"' In an in vitro/ex vivo blood- A variety of clinically significant interactions between SJW brain barrier model, the short-term effects of SJW extract and and conventional drugs have been identified, and the results

have sometimes been contradictory, such as with the anticancer interactions may cause serious or occasionally life-threatening agents imatinib''^'"''"' and irinotecan;''"*^! the anti-HIV agents in- adverse effects. In addition, herbal medicine-drug interactions in dinavir,''''^! nevirapine''^*'-'^'' and ritonavir;''^^! the antimicrobial humans are likely to be highly variable because of interindividual agent voriconazoie;''^*-'^'' the cardiovasctilar drugs digoxin,'^'-'-'""'^^' differences in nutrition habits, age, sex, genetic make-up and ivabradine,""'''! warfarin,''"*! verapamil,''*^! nifedipine''^^' and metabolizing capacity. Although there is an increase in the talinolol;''*-'! the central nervous system agents mephenytoin,''^^! available information on herbal medicine-drug interactions, amitriptyline,'"*! buspirone,'"^! methadone,''"*^! bupropion,'"^! limited data on the pharmacodynamics and pharmacokinetics midazolam,'55-56.i2i,i25,i46-i48,i62]aiprazolam,"'5! quazepam,"*'! of herbal medicines and their complex structure result in diffi- carbamazepine''^'*! and zolpidem;"^°! the digestive system agents culties in characterizing and predicting interactions, as well as omeprazole''^^! and cimetidine;''^'*! the genito-urinary system in understanding the mechanisms. The study of herbal medi- dirug finasteride;''-'^' the hypoglycaemic agent gliclazide;''^^ the cine-drug interactions is further complicated by the nature of immunosuppressants ciclosporin''25-128] ^j^^ tacrolimus;''"*'-'*"*! the herbal medicine. As the manufacturing properties of herbal oral contraceptives;''^^"'^*' the respiratory system agents theo- medicines are not strictly standardized or regulated, the in- phyliine''*^! and fexofenadine;''^^-'^^•'^''! and the statins ator- gredients identified on the labels of these products might be vastatin'"^ and simvastatin.''5'! Meanwhile, some results indicated incomplete or incorrect, and the composition could be variable no clinically relevant interactions for co-administration of SJW with from batch to batch. Although herbal medicine-drug interac- the following conventional drugs: tolbutamide,'"^-'^'' oral con- tions have been reported in several clinical studies, it is some- traceptives,''^"*! ibuprofen,''^^' mycophenolic acid,'''*'' theophyl- times diffictilt to generalize, as the effects may be ingredient iine,''**! pravastatin,''5'! carbamazepine''^-'! and prednisone.''*°! specific.'^^^! It is proposed that the same rigorous regulations In summary, a large number of studies have indicated that that apply to conventional drugs with regard to quality, safety S.rW can cause both pharmacokinetic and pharmacodynamic and efficacy should apply to herbal medicines. There is a clear interactions. The clinical implications of such SJW-drug inter- need for well designed clinical trials, pre-marketing approval re- actions depend on a variety of factors such as the duration, garding labelling and safety, and comprehensive post-marketing dosage and therapeutic range of the treatment. Hyperforin is surveillance systems for monitoring the adverse effects of herbs responsible for some of the effects on CYP and P-gp. The potential and herbal medicine-drug interactions. For example, according for SJW-drug interactions is high; therefore, patients taking pre- to the German Commission E Monographs, a few pharmaco- scribed drugs should be discouraged from taking herbal products logically potent herbs must be avoided in the presence of certain containing SJW. medical conditions. If they do not meet the Commission E Monograph guidelines, they will not be marketed in Germany. On 30 October 2005, a new Traditional Herbal Medicines Re- 3. Conclusions gistration Scheme was introduced in the United Kingdom, which is a requirement of the European Directive on Traditional Herbal Experimental and clinical data have documented that herbal Medicinal Products.'^^*' As stipulated by the EU Directive,'"*! medicines can cause pharmacokinetic and/or pharmacodynamic a large number of herbal medicines that are currently on the interactions with conventional drugs. There is accumulating evi- European market must be submitted to a registration procedure. dence that the underlying mechanisms of the observed alterations Although the use of herbal medicine may not be dangerous in drug effects and/or concentrations caused by concomitant per se, lack of communication between patients and health care herbal medicines are similar to classical drug interactions. In vitro providers may alter clinical management during co-administration. and animal studies have been widely used in attempts to predict Patients should be encouraged to tell their health care providers potential drug interactions with herbal medicine. However, dis- which herbal medicines they are taking, and the health care crepancies between results of in vitro or animal studies and those providers should be sufficiently informed to provide useful of human studies have been observed quite often.'^^'*-^^5! Never- advice for their patients. Collecting such information is critical, theless, caution must be exercised both in the absence of clinical particularly in elderly patients who are at higher risk of adverse data and with regard to reliance on lab-based evidence. interactions, especially as polypharmacy is often applied in this The clinical implications of any drug interaction depend on population.'•'•'^"^''°! Thus, increased knowledge of herbal medi- a variety of factors, such as co-administered drugs, the health cine-drug interactions would enable health care providers and status of the patients, the composition of the herbal medicine patients to be alert to the potential of interactions. This would and the applied dosage regimens. If a drug with a narrow the- also help to reduce the risk associated with any drug intake. rapeutic index (e.g. warfarin or ciclosporin) is involved, the

Finally, herbal medicines should be appropriately and compre- randomized double-blind clinical trial. Fundam Clin Pharmacol 2009 Jun; hensively labelled, including the potential for drug interactions. 23 (3): 359-65 20. Saxena A, Tripathi KP, Roy S, et al. Pharmacovigilance: effects of herbal components on human drugs interactions involving cytochrome P450. Acknowledgements Bioinformation 2008; 3 (5): 198-204 21. Kalra BS. Cytochrome P450 enzyme isoforms and their therapeutic im- This work was supported by the Natural Science Foundation of Hubei plications: an update. Indian J Med Sei 2007 Feb; 61 (2): 102-16 Province (P.R. China) [grant no. 2009CDB380], the Fundamental Research 22. Pelkonen O, Turpeinen M, Hakkola J, et al. Inhibition and induction of Funds for the Central Universities (P.R. China) [grant no. 2011JC039] and human cytochrome P450 enzymes: current status. Arch Toxicol 2008 Oct; 82 the Robert Bosch Foundation (Stuttgart, Germany). 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332. Nowack R. Review article: cytochrome P450 enzyme, and transport protein Available from URL: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do? mediated herb-drug interactions in renal transplant patients: grapefruit uri=OJ:L:2004:136:0085:0090:en:PDF [Accessed 2011 Nov 18] juice, St John's wort - and beyond! Nephrology (Carlton) 2008 Jun; 13 (4); 337. Shi S, Mörike K, Klotz U. The clinical implications of ageing for rational drug 337-47 therapy. Eur J Clin Pharmacol 2008 Feb; 64 (2): 183-99 333. Whitten DL, Myers SP, Hawrelak JA, et al. The effect of St John's wort 338. Klotz U. The elderly: a challenge for appropriate drug treatment. Eur J Clin extracts on CYP3A: a systematic review of prospective clinical trials. Br Pharmacol 2008 Mar; 64 (3); 225-6 J Clin Pharmacol 2006 Nov; 62 (5): 512-26 339. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab 334. Markowitz JS, von Moltke LL, Donovan JL. Predicting interactions between Rev 2009; 41 (2): 67-76 conventional medications and botanical products on the basis of in vitro investigations. Mol Nutr Food Res 2008 Jul; 52 (7); 747-54 340. Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab Epub2011 Apr 18 335. Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions. Life Sei 2006 Mar; 78 (18): 2105-15 336. Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products. Correspondence: Prof. Dr Ulrich Klotz, Dr Margarete Fischer-Bosch Institut Directive 2001/83/EC on the Community code relating to medicinal products für Klinische Pharmalcologie, Auerbachstraße 112,70376 Stuttgart, Germany. for human use. Official Journal of the European Union 2004 Apr 30 [online]. E-mail: [email protected]

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