HERB-DRUG INTERACTIONS: AN OVERVIEW OF MECHANISMS AND CLINICAL ASPECTS

HERB-DRUG INTERACTIONS: AN OVERVIEW OF MECHANISMS AND CLINICAL ASPECTS

Sandhya Mamindla^*, Prasad K.V.S.R.G and Bharathi Koganti

Institute of Pharmaceutical Technology, Sri Padmavathi Mahila Viswavidyalayam, Tirupati, Andhra Pradesh -517502, India

ABSTRACT: Millions of people today use herbs either as food or in the form of medicine along with prescription and non prescription medications. Although considered natural and safe, many of these herbs can interact with other medications, causing either potentially dangerous side effects and/or reduced benefits from the medication. Both pharmacokinetic and pharmacodynamic mechanisms are involved in these interactions and majority of the herb-drug interactions were found to be mediated by metabolic inductions or inhibitions. It should be understood that herbal preparations contain multiple active phytochemicals in varying proportions which can, like any other active pharmacological substance, alter the enzymatic systems, transporters and/or the physiologic processes. The purpose of this review is to discuss evidence based mechanisms and clinical implications of such herb-drug interactions and to increase awareness on herb-drug interactions by reviewing published clinical and preclinical studies. As the incidence and severity of herb-drug interactions is increasing due to a worldwide rise in the use of herbal preparations, more clinical data regarding herb-drug interactions are needed to make decisions regarding patient safety. The increasing understanding of pharmacokinetic herb-drug interactions will make health care professionals and patients pay more attention to the potential interactions.

Herb-Drug Interaction, Mechanism, CYP, P-gp, Clinical implications

INTRODUCTION: The term ‘Herbal products’ has become a colloquial term which commonly refers to all types of preparations obtained from herbs, spices, roots, stems, leaves and other non botanical materials of natural origin. They can be used therapeutically as prescription or over-the-counter medicines or even as food ¹. Due to high prices and potential side effects of synthetic drugs, people rely more on herbal drugs and this trend is growing, not only in developing countries but in developed countries too.

This upsurge in the use of phytomedicines is a global phenomenon, with more than 80% of people in Africa and Asia using herbal medicines and an increasing number in the Western world. It is estimated that 60 to 70% of the Americans are using herbal products ². According to WHO estimates, demand for medicinal plants by the year 2050 would be ~US $5 trillion ³.

One of the consequences of concurrent use of herbal medicines and allopathic drugs is the possibility of interactions. The interaction of drugs with herbal medicines is a significant safety concern, especially for drugs with narrow therapeutic indices (e.g. warfarin and digoxin), drugs with long-term regimens and which are used in the management of life threatening conditions. The risk of adverse effects due to interactions between herbal products and conventional drugs is often underestimated ⁴ by consumers due to lack of information on the safety of herbal preparations.

It has become very difficult to identify the possibility of occurrence of an interaction due to

• Availability and easy accessibility of large number of herbal products in the market

• Presence of multiple components of various pharmacological properties in the herbs

• Lack of data on the pharmacological action and mechanisms of interactions of herbal products ⁴

• Misinformation on the actual label content of herbal products ^{4, 5}

• Low potential of herb induced adverse effects

Furthermore, clinical trials addressing the safety and risk of co-administered drugs with certain herbal products showed that the outcomes are greatly affected by pharmacogenetics and/or individual variability ^{6, 7}. Due to the clinical significance of herbal interactions with conventional drugs, it is important to identify herbs and drugs that may interact with each other. This paper updates our knowledge on herb-drug interactions with an emphasis on mechanistic and clinical considerations.

2. Mechanisms Involved in Herb-Drug Interactions:

Knowledge of the mechanism by which a given herb-drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and methods of circumventing the interaction. Herb–drug interactions based on the mechanism involved are classified into pharmacokinetic and pharmacodynamic interactions.

 2.1 Pharmacokinetic interactions:

Pharmacokinetic interactions are caused by alterations in the absorption, distribution, metabolism, or excretion of drugs which results in altered levels of the drug or its metabolites. 

2.1.1 Herb-drug interactions at absorption level

2.1.1.1 Influence of herbs on efflux transporters:

Several reports have indicated that human drug efflux transporters, acting alone or together with drug metabolising enzymes, play an important role in oral drug bioavailability ⁸. Efflux of drugs against a steep concentration gradient is mediated by the ATP binding cassette (ABC) transporters, mostly located in the canalicular membrane of the intestinal epithelium, human liver, kidney or the endothelium of blood capillaries of the brain ⁹. ABC transporters are relatively easily modulated by factors such as therapeutic drugs and herbal medicines, foods and beverages ¹⁰.

The efflux transporters play a role in limiting influx of xenobiotics, thus preventing the intracellular accumulation of their own substrates. The activity of the efflux transporters on interaction with herbs may be inhibited by competitive or non-competitive mechanisms, which may potentially lead to toxic blood plasma concentrations of drugs that are normally substrates. Conversely, the induction of efflux transporters by herbs would result in sub-therapeutic plasma drug levels leading to treatment failure ¹¹.

The mechanisms and examples of influence of the herbs on different efflux transporters is explained as follows

(i) P- Glyco protein (P-gp):

P-gp is also known as multi-drug resistance protein 1 (MDR1) or ABC subfamily B, member 1 ¹². P-Glycoprotein has a significant role in oral drug absorption and decreases bioavailability because intact drug molecules are pumped back into the gastrointestinal tract lumen and exposed multiple times to enterocyte metabolism using ATP as an energy source. Within hepatocytes, P-gp mostly pumps hydrophobic (neutral or positively charged) substances into the bile and this efflux occurs in many other organs such as the kidney as well ¹². P-gp plays an important role in regulating the absorption, distribution and elimination/ reabsorption of many clinically important therapeutic substances. Modulation of P-gp by herbal constituents may, therefore, involve direct interaction with one or more binding sites on the P-gp molecule through competitive or non-competitive inhibition or induction of the efflux of drugs. Phytochemicals may also inhibit ATP binding, hydrolysis or coupling of ATP-hydrolysed molecules, therefore, depleting the energy which drives the translocation of P-gp bound substrate drugs ⁷. Phytoconstituents that induce P-gp will in turn potentiate the substrate-induced-fit of drugs resulting in even much higher efflux of most P-gp substrates ¹³.

• Some examples of herb drug interactions modulated by P- gp:
• P-glycoprotein confers high levels of resistance to bulky amphipathic natural product type drugs such as paclitaxel, Vinca alkaloids, anthracyclines, camptothecins, and epipodophyllotoxins. Alisol B23-acetate from Alisma orientalis has increased anticancer activity of vinblastine, doxorubicin, rhodamine-123 by reducing P-gp efflux activity in vitro in MDR cell lines (HepG2-DR and K562-DR) ¹⁴.

• Citrus paradisi (Grapefruit juice) was found to inhibit P-gp rhodamine-123 efflux in vitro in Caco-2 cells ¹⁵ and in vivo in healthy volunteers ¹⁶. It was also found to increase the bioavailability of nifedipine in vivo in rats ¹⁷ and talinolol in vitro in Caco-2 cells ¹⁸.

• A few divergent results on the modulation of P-gp by Allium sativum (garlic) have been reported. Aged garlic extract has been shown to induce P-gp, MRP2, BCRP and OATPs activities ¹⁹. The diallyl sulphide which is an active constituent in garlic can also induce P-gp and MRP2 expression in vitro ²⁰. Interestingly, diallyl trisulfide has been shown to inhibit the activity and expression of P-gp in a recent study ²¹.

• Camellia sinensis (green tea) contains catechins that modulate P-gp transport in vitro and in vivo either through inhibition or activation by means of a heterotropic allosteric mechanism ²². 6-gingerol inhibited P-gp-mediated efflux of daunorubicin and rhodamine-123 in KB-C2 cells ²³. Thein vitro or in vivo activity of human P-gp was significantly reduced by Ginkgo biloba (ginkgo) extract ⁸.

Other drug efflux transporters:

(ii)  Multi-drug resistance-associated protein-2 (MRP2):

MRP2 or ABC subfamily C member 2 (ABCC2) is functionally a canalicular multi-specific organic anion transporter ¹¹. MRP2 is localised in the bile canalicular membrane of hepatocytes and part of the 9-member human subfamily of multi-drug resistance-associated proteins (MRP1 - MRP9). The expression of MRP2, unlike P-gp, is high in the proximal and very low in the distal region of human intestines ¹¹. MRP2 is found in many cancer cell lines and tumours obtained from patients suggesting that MRP2 may contribute to resistance against treatment with chemotherapeutic drugs.

The ATP-dependent MRP family primarily transports hydrophobic anionic conjugates and extrudes hydrophobic neutral molecules. In particular, MRP2 exports relatively large hydrophilic compounds including the glucuronide, glutathione and sulfate conjugates of endogenous and exogenous compounds from liver cells into the bile ¹². MRP2 is also responsible for the biliary secretion of organic anions such as acetaminophen glucuronide and camptothecin ²⁴.

(iii) Breast cancer resistance protein (BCRP):

Another important drug efflux transporter is the breast cancer resistance protein (BCRP), member 2 on the ABC White (ABCG) subfamily, which contains ‘half-transporters’ ²⁵. BCRP or ABCG2 is also known as placenta-specific ABC gene or as mitoxantrone resistance gene. BCRP is expressed in a variety of tumour cells and many normal human tissues. BCRP has only one nucleotide binding domain, namely the ABC at the amine terminus and a single set of transmembrane domain containing six transmembrane regions at the carboxyl terminus ²⁶. BCRP confers resistance to a narrower range of anticancer agents than P-glycoprotein and MRP.

• Some examples of herb drug interactions modulated by MRP2 and BCRP:
• Relatively little information about the effects of herbal products on efflux transporters other than P-gp is available. However, herbs that show ability to modulate P-gp activity may also affect related efflux transporters. For instance, herbs with interactions that occur by the same pathway as grapefruit juice may also modulate MRP2 and BCRP. It is, therefore, suggested that more in vitro and in vivo data are required to be conclusive in terms of the significance of these pathways of herb--drug pharmacokinetic interactions on the bioavailability and consequently on the pharmacological effect and toxicity of affected drugs.

• Cooray et al. report that some plant-derived polyphenols that interact with P-gp can also modulate BCRP activity in vitro ²⁷. Meanwhile, it was reported that flavonoids like apigenin, biochanin A, genistein, kaempferol from Silybum marianum enhance the accumulation of the BCRP substrate mitoxantrone by inhibition of BCRP in vitro and in vivo in MCF-7 M-X100 cells ²⁸. On the other hand, BCRP does not confer resistance to theVinca alkaloids, epipodophyllotoxins, paclitaxel, or cisplatin²⁹.

(iv) Influence of herbs on uptake carrier proteins:

SLC transporters such as organic anion transporters OATs), organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) mainly mediate uptake of substrates in cells. These transporters are involved in oral bioavailability and intestinal, hepatobiliary and renal excretion of a concomitant drug.

Examples:

• Naringin, a furanocoumarinic phytochemical in Citrus paradisi juice, inhibits the influx or uptake active transporter organic anion transporting polypeptide (OATP) 1A2 in vitro consequently lowering the bioavailability of certain drugs ^{30, 31}. A polyphenolic catechin, (-)-epigallocatechin gallate found in Citrus sinensis and Echinacea purpurea (Echinacea), showed potential to inhibit OATP-B in vitro resulting in reduced drug carrier-mediated transport into the cell possibly lowering drug bioavailability ³².

• Inhibition of OATP1 and OATP3 by components of Citrus sinensis (Seville orange) and Malus domestica (apple) juices may decrease drug uptake and lead to sub-therapeutic drug concentrations in vitro and in vivo ³³. On the other hand, Takano et al. suggest that over-induction of OATP may increase drug uptake and lead to toxic blood drug concentrations ¹¹.

 2.1.1.2 Herb interactions on gastrointestinal motility:

Altered gastrointestinal motility following consumption of herbal products can have a marked impact on the therapeutic outcomes of treatment with conventional drugs. Herbal induced diarrhoea, which results in a shorter transit time of the drug along the gastrointestinal tract, reduces contact time with the gastrointestinal epithelium and, therefore, leads to lower drug absorption.

• Ginkgo biloba leaf extract containing flavonoids and terpenoids, Zingiber officinale (ginger) and Piper methysticum (kava) extracts increase gastrointestinal motility in vitro and in vivo ^{34, 35}. Echinacea purpurea and Hypericum perforatum which are known to induce diarrhoea as side effects may also affect drug absorption in a similar manner ³⁵. Sennosides were found to increase the GIT transit rate and motility in vitro in mouse colon cells and Caco-2 cells respectively. The herbs can also increase the activity of laxatives indicated for constipation and antagonise the action of antidiarrhoeal agents.

 2.1.1.3 Herb interactions through complex formation:

Formation of insoluble herb-drug complexes in the gastrointestinal tract can significantly reduce the bioavailability of co-administered drugs resulting in sub-therapeutic effects. Some antibiotics such as flouroquinolones and tetracyclines bind to iron, calcium, calcium-fortified foods and supplements including herbal products and co-administered antacids.

The formation of herb-drug complexes implies that the emergence of resistance in the treatment of diseases like tuberculosis and HIV/AIDS may have long-term implications on the quality-adjusted life years of the patient. An example is that of phenytoin that may bind to iron, calcium and magnesium in antacids and herbal preparations resulting in possible injuries due to uncontrolled epilepsy.

 Examples:

• Fibres such as psyllium and alginates may chelate iron and drugs such as metformin and glibenclamide as shown by both in vitro and in vivo studies, thus, reducing their clinical efficacy ³⁶. For instance, the absorption of iron from an iron-fortified meal was significantly reduced by Capsicum annum ³⁷. The authors postulated that the reduction in iron absorption was due to iron binding to chilli polyphenols such as capsaicin. In view of the potential chelating and complexation effects of mineral components in certain herbal preparations, they should be administered either 2 h before or 2 h after the dose of the interacting drug. The effect of herbs on pharmacokinetics of drugs via the mechanism of complex formation remains inconclusive due to a lack of in vivo clinical trials on this specific type of herb-drug interaction.

 2.1.2 Herb-drug interactions at metabolism level

Metabolism-mediated herb-drug interactions are performed primarily by the cytochrome P450 (CYP) family of metabolic enzymes (phase I enzymes) and non CYP enzyme systems (phase II enzymes) such as uridine diphosphoglucuronosyl transferases (UGTs). Pharmacokinetic herb-drug interactions occur when drug metabolic enzymes are induced or inhibited by concomitant herbal medicines ³⁸. Inhibition of metabolic enzymes occurs when herbal medicines are able to decrease the expression or activities of metabolic enzymes in a competitive or non-competitive manner. Induction of metabolic enzymes is a much slower process, in which herbal medicines promote gene activation and increase the gene or protein levels of the relevant metabolic enzyme. The CYPs induction is modulated by ligand-dependent transcription activation of nuclear receptors including pregnane X receptors (PXR) and constitutive androstane receptors (CAR), etc. The inhibition and induction process of enzymes are reversible and enzyme levels can return to the normal levels after stopping the administration of herbal medicines.

• Examples of enzyme induction:
• Induction of CYP enzymes often results in therapeutic failure because of lower plasma concentrations of the drugs. One of the well-studied herb medicines, St. Johns Wort (Hypericium perforatum) induces CYP3A4 and CYP2B6, resulting in a decrease in plasma levels of irinotecan and imatinib, which are two chemotherapeutic drugs ^{39, 40}. Hyperforin, a major active ingredient of St. John’s wort, is the agonist of PXR which can modulate CYP3A4 expression ⁴¹. In mouse, the administration of garlic juice for 8 days induced the protein expression of CYP1A2 and 2E1 ⁴². In human, the in vivo activity of CYP3A4 was increased, by ginkgo extract ⁴³.

• Examples of enzyme inhibition:
• In general, inhibition of CYP enzymes would lead to an increase in plasma concentrations of the concomitant drug, and recognizable, increased toxicity. Furano coumarins (e.g., naringenin and bergamottin) in paradisi juice and C. sinensis increase the plasma concentration of a number of drugs including cyclosporine, terfenadine, midazolam and felodipine through mechanism-based inhibition of the CYP3A4 enzyme as ‘suicide substrate’ in vitro and in vivo in humans ^{44, 45}.

• Garlic extract inhibitedin vitro CYP2C9, 2CY2C19, CYP3A4, 3A5, and 3A7 aactivity, while it did not affect the CYP2D6 activity, and increased the activity in recombinant human CYP isozyme system ²⁰.

• The in vitroactivities of CYP1A2, 2C9, and 2E1 were decreased by ginkgo extract. The activity of CYP1A2 and 2C9 was not significantly changed by ginkgolides, while that of CYP3A4 was increased by ginkgolide A via pregnane X receptor ⁴³.

• Ginger extract inhibited CYP2C9 and 3A4 activities in recombinant human CYP isozyme system ⁴⁶ and CYP2C19 activity in human liver microsomes ⁴⁷.

 2.1.3 Herb-drug interactions at distribution level:

Herbs such as meadowsweet and black willow, which contain pain-reducing salicylates, may displace highly protein bound drugs such as warfarin and carbamazepine, thus increasing the adverse effects of these drugs. These products should not be taken concurrently ⁴⁸.

 2.1.4 Herb-drug interactions at elimination level:

The major routes for elimination of drugs remain the kidney and bile, but there are no significant herb-drug interactions through bile elimination. Drugs that are chiefly excreted by the kidneys can get involved in herb-drug interactions by different mechanisms such as competition at active transport sites, or alterations in glomerular filtration, passive renal tubular reabsorption or active secretion and urinary pH ⁴⁸. The mechanism of herbal diuresis is complex and non-uniform. Certain herbs increase the glomerular filtration rate but do not stimulate electrolyte secretion while some others act as direct tubular irritants ⁴⁹.

• Some examples of herbs capable of interacting with renal functions and drug elimination are: Impila (Callilepis laureola) causes damage to the proximal convoluted tubules and the loop of henle and was found to be be hepatotoxic ⁷⁸. Uvaursi (Arctostaphylos uva ursi), goldenrod (Solidago virgaurea), dandelion (Taraxacum officinale), juniper berry (Juniperus communis), horsetail (Equisetum arvense), lovage root (Levisticum officinale), parsley (Petroselinum crispum), asparagus root (Asparagus officinalis), stinging nettle leaf (Urtica dioica), alfalfa (Medicago sativa) were found to have diuretic property and may increase the renal elimination of other drugs ⁵⁰.

 2.2 Pharmacodynamic interactions:

Pharmacodynamic interactions are those herb-drug interactions that cause changes in pharmacological responses (e.g., changes in the physiological effect and mechanism of action of the drug on the body and altered relationship of the drug concentration to drug action). Pharmacodynamic interactions may result in augmentation or inhibition of the pharmacological activity of a co-administered drug. Herb-drug pharmacodynamic interactions would, therefore, involve changes in the pharmacological effects of the drug through additive, synergistic or antagonistic actions ⁵¹.

The problem lies in the fact that any single herbal preparation may contain several components, all of which may have unknown biological activities; therefore, an herbal medicine can potentially mimic, increase, or reduce the effects of co-administered drugs through simultaneous effects on the same drug targets ⁵². Unfavorable effects may incur, causing target toxicity, if the effect of the drug in combination with the herbal medicine is enhanced synergistically or by additive effects; this has been observed clinically with the anticoagulant warfarin.

In contrast, herbal medicines may contain antagonistic components, which would reduce drug efficacy and cause potential therapeutic failure as with statin therapies. Acting on or competition for the same drug target is the cause of synergistic or antagonistic effects between herbal medicines and drugs that are co-administered. For example, herbal medicines such as garlic, ginger, ginkgo, ginseng, alfalfa (Medicago sativa), chamomile (Matricaria recutita), and danshen may enhance the anticoagulant activity of warfarin by targeting the same vitamin K epoxide reductase target or other critical components in the coagulation cascade ⁵³. Thus, all of these herbal products may increase the risk of bleeding in patients on chronic warfarin therapy. Aspilia africana (Alkaloids, tannins) when used along with artemisinin, chloroquine in malaria was found to antagonise their effects ⁵⁴.

3. Clinical Outcomes of Herb-Drug Interactions:

When a drug’s clearance is significantly altered, or its drug targets are the same as the herbal components, a clinically important herbal interaction with the drug may occur. The clinical outcome of an herb-drug interaction varies, being well tolerated, mild, or sometimes lethal.

 3.1 Altered Drug Clearance:

Herbal medicines that are able to modulate intestinal and hepatic CYPs and P-gp often alter the oral absorption, bioavailability, systemic exposure and clearance of co administered drugs ⁵⁵.

• For example, Milk thistle that contains potent CYP3A4, BCRP and P-gp inhibitor (silibins and silymarin) and would increase the oral bioavailability and decrease the clearance of co administered drugs. In studies on the effect of its active component silibinin on the pharmacokinetics of the anti-tuberculous drug pyrazinamide, Wu and Tsai suggested that the herb altered the hepatobiliary elimination of pyrazinamide ⁵⁶. Rajnarayana et al., showed that another component, silymarin caused an increased clearance of metronidazole and its metabolite hydroxymetronidazole, thereby decreasing the half life of this antiprotozoal agent ⁵⁷. Garlic preparations decrease the plasma concentrations of saquinavir ⁵⁸. Consequently, drug efficacy may be changed and toxicity may occur.

 3.2 Altered Drug Efficacy:

There are limited clinical studies addressing the effect of combined herbal medicines on drug efficacy due to pharmacokinetic and/or pharmacodynamic mechanisms. When the systemic exposure of a drug is significantly increased or reduced by herbal medicines, the clinical response to this drug may change. A direct additive, synergistic or antagonistic interaction between the drug and herbal medicines will also alter the magnitude of drug response.

• Many herbal medicines such as danshen (Salvia miltiorrhiza), dong quai(Angelica sinensis), fever few (Tanacetum parthenium), goldenseal (Hydrastis canadensis), ginseng, horse chestnut (Aesculus hippocastanum), red clover (Trifolium pratense), tumeric, passionflower (Passiflora incarnata), and ginkgo can enhance the anticoagulant effect of warfarin ⁵³.

• There is greater chance for potentiation of hepatotoxicity when hepatotoxic herbs like chapparal (Larrea tridentata), germander (Teucrium chamaedrys), echinacea (Echinacea purpurea) are co administered with hepatotoxic drugs such as non steroidal anti – inflammatory drugs (NSAIDs), ketoconazole and methotrexate.

3.3 Occurrence of Adverse Effects:

An herb-drug interaction may lead to adverse reactions that may be mild, moderate, or even life-threatening. Mild to moderate adverse events due to herb-drug interactions are generally well tolerated, but some herb-drug interactions may cause severe adverse reactions. For most of the harmful interactions, pharmacodynamic mechanism may provide an explanation, although altered pharmacokinetics may also contribute to the interactions. The clinical outcome of herb-drug interactions depends on factors that are related to the co-administered drug, herbal medicine and patients.

Generally, a doubling or more in drug plasma concentration has the potential for enhanced drug effects and/or appearance of adverse effects. However, less marked changes may still be clinically important for drugs with a steep concentration-response relationship or a narrow therapeutic index (e.g. warfarin). In most cases, the magnitude of herb-drug interactions varies markedly among individuals, depending on inter-individual differences in the expression, activity of drug metabolizing enzymes and transporters, co-medication with other drugs, age and many of other physiopathological factors.

• There are several reports where ginseng induced mania when used concomitantly with phenelzine ⁵⁹ and ginkgo raised blood pressure when combined with a thiazide diuretic ⁶⁰ and caused coma when combined with trazodone, an atypical antidepressant ⁶⁰.

• Enhanced anticoagulation and bleeding was observed when patients on chronic warfarin therapy consumed danshen ( miltiorrhiza) ⁶¹.

• Kava (Piper methysticum) caused a semicomatose state when given concomitantly with alprazolam ⁶². A patient with Parkinson’s disease taking levodopa in combination with kava had increased duration and number of “off” periods ⁶³. This may be explained by the dopamine antagonistic activity of kava.

• Ephedra is known to have risk of myocardial ischemia, tachycardia, hypertension and it may also produce ventricular arrhythmias when combined with anesthetics ⁶⁴.

4. Patient Counseling about Herb-Drug Interactions:

Use of herbal and dietary supplements is extremely common. In one US survey of adults who regularly take prescription medication, 18·4% reported the concurrent use of at least one herbal product or high-dose vitamin. A survey of 515 users of herbal remedies in the UK found that 26% would consult their general practitioner for a serious adverse drug reaction associated with a conventional over the counter medicine, but not for a similar reaction to a herbal remedy ⁶⁵. Clinicians must ask patients about their use of herbs in a non-judgmental, relaxed way. A disapproving manner will ensure only that a patient will conceal further use. The patient should be treated as a partner in watching out for adverse reactions or interactions and should be told about the lack of information on interactions and the need for open communication about the use of herbal remedies. Formulation, brand, dose and reason for use of herbs should be documented on the patient’s charts and updated regularly.

5. The Other Side of Herb – Drug Interactions:

Beneficial effects: Along with an exhaustive list of herb – drug interactions which need special precautions there are some herb - drug combinations which are quite safe. In some cases, herbs have been shown to mitigate or prevent adverse effects associated with drugs. For example, aromatic herbs such as ginger can be used to prevent drug-induced nausea; milk thistle can be used to prevent the liver toxicity associated with drugs.

In addition, the scientific studies have proven that capsaicin reduces gastric mucosal damage induced by aspirin ⁶⁶. Hawthorn is useful for angina and it is as an alternative to digitalis in Europe. A study on digoxin and hawthorn revealed that their combined use has no significant interaction and they can be used safely ³³.

Animal studies have shown that the combination of aqueous extract of Chinese medicinal plant Tripterygium wilfordi and cyclosporine significantly increases the heart and kidney allograft survival compared to cyclosporine alone ⁶⁷_. It is also proven that garlic prevents the formation of toxic metabolites of paracetamol, co-administration of ginkgo with antipsychotics (haloperidol) in chronic schizophrenic patients reduces extra pyramidal side effects associated with haloperidol ⁶⁸.

Centella asiatica can also be used as an adjunctive medication for patients with epilepsy due to its additive anticonvulsant activity ⁶⁹. Momordica charantia is reported to augment the hypoglycemic effect of rosiglitazone which can be used to reduce the dose of rosiglitazone to achieve enhance therapeutic effect with minimum side effects ⁷⁰. Piperine can be used as bioavailability enhancer for several drugs and studies bolster that piperine enhances the bioavailability of propranolol which can be used as a means to achieve better therapeutic control and improved patience compliance ⁷¹.

In the similar lines Ginseng is considered to be potent adjuvant for delivery of vaccines which have been proven to induce higher or similar antibody titres than vaccines adjuvanted with aluminium hydroxide ⁷². Further, studies also prove that Rosemary (Rosmarinus officinalis) has chemopreventive effect as it increases efflux and intracellular accumulation of doxorubicin and vinblastine ⁷³. In vitro studies also revealed that silybinin enhances the antitumour activity of cisplatin ⁷⁴. All these data suggest that synergistic potential between herbal medicines and drugs can be therapeutically advantageous, clearly stressing the need for extensive work to be done in this area.

 CONCLUSION: There is a continued global increase in the use of herbal products and supplements which has led to notable increase in the incidence of herb – drug interactions. Herbs may interact with drugs either by pharmacokinetic or pharmacodynamic mechanisms. Pharmacokinetic interactions involve different mechanisms that influence the absorption, metabolism, distribution and elimination of drugs. Any new drugs that are substrates for CYP3A4 and/or Pgp have a potential to cause herb-drug interactions. When there is an increasing use of herbal medicines by patients worldwide, clinicians should have a better knowledge on herb-drug interactions and adopt proper strategies to minimize harmful herb-drug interactions. Timely identification of drugs that interact with herbal medicines and the underlying mechanism is important. If these drugs have to be used in combination with the herbs, dose adjustment may be needed and discontinuation of therapy is necessary when toxic drug-herb interactions occur. Both patients and clinicians should be educated on the clinical significance of herb-drug interactions.

ACKNOWLEDGEMENTS: The authors are grateful to the digital library facilities provided by IPT, SPMVV which helped in writing this review.

 CONFLICT OF INTEREST: It is to specifically state that “No Competing interests are at stake and there is No Conflict of Interest” with other people or organizations that could inappropriately influence or bias the content of the paper.

REFERENCES:

1. Obiageri O. Obodozie (2012). Pharmacokinetics and Drug Interactions of Herbal Medicines: A Missing Critical Step in the Phytomedicine/Drug Development Process, Readings in Advanced Pharmacokinetics - Theory, Methods and Applications, Dr. Ayman Noreddin (Ed.), ISBN: 978-953-51-0533-6
2. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the
3. United States, 1990-1997: results of a follow-up national survey. 1998; 280: 1569- 1575.
4. Sharma A.B., Global medicinal plants demand may touch $5 trillion by 2050. Indian Express 2010
5. Colalto C. Herbal interactions on absorption of drugs: mechanisms of action and clinical risk Pharmacol Res 2010;62:207-27
6. Vermaak I, Hamman JH, Viljoen AM. High performance thin layer chromatography as a method to authenticate Hoodia gordonii raw material and products. SA J Bot 2010;76:119-24
7. Lin JH, Lu AYH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet.1998;35:361-90
8. Zhang L, Strong JM, Qiu W, et al. Scientific perspective on drug transporters and their role in drug interactions. Mol Pharm 2006;3:62
9. Hellum BH, Nilsen OG. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin. Pharmacol Toxicol 2008;102:466-75
10. Sadeque AJ, Wandel C, He H, et al.Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 2000;68:231-7
11. Food and Drug Administration (FDA). Guidance for industry. Drug interactions studies: study design, data analysis, and implications for dosing and labelling. Draft Guidance. Available from: http://www.fda.gov/ downloads/ Drugs/Guidance Compliance Regulatory Information/Guidances/ucm072101.pdf
12. Takano M, Yumoto R, Murakami T, Inui K. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 2006;109:137-61
13. Chan LM, Lowes S, Hirst BH. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 2004;21:25-51 Mandava N, Oberol RK, Minocha M, Mitra AK. Transporter targeted drug delivery. J Drug Del Sci Technol 2010;20:89-99
14. Van Asperen J, Van Tellingen O, Beijnen JH. The role of mdr1a P-glycoprotein in the billiary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metab Dispos2000;28:264-7
15. Wang C, Zhang JX, Shen XL, et al. Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate. Biochem Pharmacol 2004;68:843-55
16. Lim SK, Lim LY. Effects of citrus fruit juices on cytoxicity and drug transport pathways of Caco-2 cell monolayers. Int J Pharm 2006;302:42-50
17. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and Seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 2002;71:1149-60
18. Mohri K, Uesawa Y. Effects of furanocoumarin derivatives in grapefruit juice on nifedipine pharmacokinetics in rats. Pharm Res 2001;18:177-82
19. Spahn-Langguth H, Langguth P. Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol. Eur J Pharm Sci 2001;12:361-7
20. Berginc, K.; Zakelj, S.; Ursic, D.; Kristl, A. Aged garlic extract stimulates p-glycoprotein and multidrug resistance associated protein 2 mediated effluxes. Pharm. Bull., 2009, 32(4), 694-699.
21. C. Foster, M. S. Foster, S. Vandenhoek et al., An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic,”Journal of Pharmacy and Pharmaceutical Sciences, vol. 4, no. 2, pp. 176–184, 2001
22. Arora, A.; Seth, K.; Shukla, Y. Reversal of P-glycoproteinmediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver. Carcinogenesis, 2004, 25(6), 941-949
23. Budzinski JW, Foster BC, Trudeau VL, et al. The interaction of selected phytochemical, HIV drugs, and commercial-source herbal teas and capsules with human cytochrome P450 3A4 and P-glycoprotein. Pharm Biol 2008;46:53-65
24. Nabekura, S. Kamiyama, and S. Kitagawa, “Effects of dietary chemopreventive phytochemicals on P-glycoprotein function,”Biochemical and Biophysical Research Communications, vol. 327, no. 3, pp. 866–870, 2005
25. H. Choi, Y.-W. Chin, and Y. G. Kim, “Herb-drug interactions: focus on metabolic enzymes and transporters,” Archives of Pharmacal Research, vol. 34, no. 11, pp. 1843–1863, 2011
26. Ozvegy C, Litman T, Szakacs G, et al. Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun 2001;285:111-17
27. Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003;22:7340-5
28. Cooray HC, Janvilisri T, Van Veen HW, et al. Interaction of the breast cancer resistance protein with plant polyphenols. Biochem Biophys Res Commun 2004;371:269-75
29. Zhang S, Yang X, Morris ME. Comnined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res2004;21:1263-73
30. Allen JD, Schinkel AH. Multidrug resistance and pharmacological protection mediated by the breast cancer resistance protein (BCRP/ABCG2)Mol Cancer Ther. 2002; 1:427–434.
31. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther2002;71:11-20
32. Bailey DG, Dresser GK, Leake BF, et al. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 2007;81:495-502
33. Kobaashi D, Nozawa T, Imai K, et al. Involvement of human organic anion transporting polypeptide OATPB (SLC21A9) in pH-dependent transport across intestinal apical membrane.J Pharmacol Exp Ther 2003;306:703-8
34. Farkas D, Greenblatt DJ. Influence of fruit juices on drug disposition; discrepancies between in vitro and clinical studies. Expert Opin Drug Metab Toxicol 2008;4:381-93
35. Cass H. Herbs for the Nervous System: Ginkgo, Kava, Valerian, Passion flower. Semin Integrat Med 2004;2:82-8
36. Colalto C. Herbal interactions on absorption of drugs: mechanisms of action and clinical risk assessment. Pharmacol Res 2010;62:207-27
37. Chiesara E, Borghini R, Marabini L. Dietary fibre and drug interactions. Eur J Clin Nutr 1995;49(Suppl 3):S123-8
38. Tuntipopipat S, Judprasong K, Zeder C, et al. Chili, but not turmeric, inhibits iron absorption in young women from an iron- Fortified composite meal. J Nutr2006;136:2970-4
39. Mukherjee, P.K.; Ponnusankar, S.; Pandit, S.; Hazam, P.K.; Ahmmed, M.; Mukherjee, K. Botanicals as medicinal food and their effects on drug metabolizing enzymes. Food Chem. Toxicol., 2011, 49(12), 3142-3153.
40. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-95
41. Williamson EM. Drug interactions between herbal and prescription medicines. Drug Safety 2003;26(15):1075-92
42. Gödtel-Armbrust, U.; Metzger, A.; Kroll, U.; Kelber, O.; Wojnowski, L. Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John's wort. Naunyn Schmiedebergs Arch. Pharmacol., 2007, 375(6), 377-382.
43. Kishimoto, M. Ueda, H. Yoshinaga, K. Goda, and S.-S. Park, “Combined effects of   ethanol and garlic on hepatic ethanol metabolism in mice,” Journal of Nutritional Science and Vitaminology, vol. 45, no. 3, pp. 275–286, 1999
44. M. Robertson, R. T. Davey, J. Voell, E. Formentini, R. M. Alfaro, and S. R. Penzak, “Effect of Ginkgo bilobaextract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects,”Current Medical Research and Opinion, vol. 24, no. 2, pp. 591–599, 2008.
45. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998;46:101-10
46. Zhou S, Lim LY, Chowbay B. Herbal modulation of P-glycoprotein. Drug Metab Rev 2004;36:57-104
47. H. Ali, G. Blunden, M. O. Tanira, and A. Nemmar, “Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinaleRoscoe): a review of recent research,” Food and Chemical Toxicology, vol. 46, no. 2, pp. 409–420, 2008.
48. S. Kim, S. Y. Kim, and H. H. Yoo, “Effects of an aqueous-ethanolic extract of ginger on cytochrome P450 enzyme-mediated drug metabolism,”Pharmazie, vol. 67, no. 12, pp. 1007–1009, 2012.
49. Isnard B. C., Deray G., Baumelou A., Le Quintrec M., Vanherweghem J.L. Herbs and the kidney.  J. Kidney Dis. 44, 1–1110.1053/S0272-6386(04)00714-0, 2004
50. Crosby E. C., Dolan R. L., Benson J. E., Luetkemeier M. J., Barton R. G., Askew E. W. Herbal diuretic induced dehydration and resting metabolic rate. Sci. Sports Exerc. 33, S163.10.1097/00005768-200105001-00923, 2001
51. Wojcikowski K., Wohlmuth H., Johnson D. W., Rolfe M., Gobe G. An in vitro investigation of herbs traditionally used for kidney and urinary system disorders: potential therapeutic and toxic effects. Nephrology (Carlton) 14, 70–7910.1111/j.1440-1797.2008.01017.x , 2009
52. Izzo, A. A. Herb-drug interactions: an overview of the clinical evidence. Clin. Pharmacol., 2005, 19(1), 1-16.
53. Fugh-Berman, A., Herb-drug interactions. Lancet, 2000, 355, 134-138.
54. Greenblatt, D.J.; von Moltke, L.L., Interaction of warfarin with drugs, natural substances, and foods. Clin. Pharmacol., 2005, 45, 127-132
55. Abii T. A., Onuoha E. N. The chemical constituents of the leaf ofAspilia africana as a scientific backing to its tradomedical potentials.  J. 6, 28–3010.3923/aj.2011.28.30, 2011
56. Gaudineau, R. Beckerman, S. Welbourn, and K. Auclair, “Inhibition of human P450 enzymes by multiple constituents of theGinkgo biloba extract,” Biochemical and Biophysical Research Communications, vol. 318, no. 4, pp. 1072–1078, 2004.

57. Wu JW, Tsai TH. Effect of silibinin on the pharmacokinetics of pyrazinamide Rajnarayana K, Reddy MS, Vidyasagar J, Krishna DR. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole Arzneimittelforschung, 54, 2004, 109-113.
58. Piscitelli, S. C.; Burstein, A. H.; Welden, N.; Gallicano, K. D.; Falloon, J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Infect. Dis., 2002, 34(2), 234-238.
59. Jones, B. D.; Runikis, A. M. Interaction of ginseng with phenelzine. Clin. Psychopharmacol., 1987, 7(3), 201-202.
60. Shaw, D.; Leon, C.; Kolev, S.; Murray, V. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995).Drug Saf., 1997, 17(5), 342-356.
61. Wittkowsky, A. K. Dietary supplements, herbs and oral anticoagulants: the nature of the evidence. Thromb. Thrombolysis, 2008, 25(1), 72-77.
62. Almeida, J. C.; Grimsley, E. W. Coma from the health food store interaction between Kava and alprazolam. Intern. Med., 1996, 125(11), 940-941.
63. Schelosky, L.; Raffauf, C.; Jendroska, K.; Poewe, W. Kava and dopamine antagonism. Neurol. Neurosurg. Psychiatry, 1995, 58(5), 639-640.
64. Kaye A, Clarke R, Sabar R, Vig S, Dhawan KP, Hofbauer R and Kaye AM. Herbal medicines: Current trends in anesthesiology practice – A hospital based survey. Clin. Anesth. 12: 468-471,2000
65. Barnes J, Mills SY, Abbott NC, et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face to face interviews with515 users of herbal remedies. Br J Clin. Pharmacol 1998; 45: 496–500
66. Yeoh KG, Kang JY, Yap I, Guan R, Tan CC, Wee A, and Teng CH. Chilli protects against aspirin-induced gastro duodenal mucosal injury in humans. Dis. Sci. 40: 580-583,1995
67. Wang J, Xu R, Chen Z, and Fidler JM. Immunosuppressive activity of Chinese medicinal plant Tripterygium wilfordi. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination with cyclosporine. 70: 447-455, 2000
68. Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, and Cao LY. A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. Clin. Psych. 62: 878-883, 2001
69. Vattanajun A, Watanabe H, Tantisara MH, and Tantisara B. Isobolographically additive anticonvulsant activity between Centella asiatica’s ethyl acetate fraction and some antiepileptic drugs. Med. Assoc. Thai. 88: 131-140, 2005
70. Susan NN, Mohammed A and Prasad SV. Pharmacodynamic interaction of Momordica charantia with rosiglitazone in rats. Biol. Interac. 177: 247-253, 2009
71. Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK and Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. J. Clin. Pharmacol. 41: 615-617,1991
72. Rivera E, Daggfeldt A, and Hu S. Ginseng extract in aluminium hydroxide adjuvanted vaccines improves the antibody response of pigs to porcine parvovirus and Erysipelothrix rhusiopathiae. Immunol. Immunopathol. 91: 19-27, 2003.
73. Huang MT, Chi TH, Zhi YW, Thomas F, You-Rong L , Kathe S, Wei M, Constantino G, Jeffrey DL and Allan HC. Inhibition of Skin Tumorigenesis by Rosemary and Its Constituents Carnosol and Ursolic Acid. Cancer Res. 54: 701-708 ,1994
74. Scambia G, De Vincenzo R, Ranelletti FO, Panici PB, Ferrandina G, D'Agostino G,    Fattorossi A, Bombardelli E, and Mancuso S. Antiproliferative effect of silybin on gynecological malignancies synergism with cisplatin and doxorubicin. Eur. J. Cancer. 32: 877- 882, 1996.
    

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How to cite this article:

Mamindla S, Prasad KVSRG and Koganti B: Herb-Drug Interactions: An Overview of Mechanisms and Clinical Aspects. Int J Pharm Sci Res 2016; 7(9): 3576-86.doi: 10.13040/IJPSR.0975-8232.7(9).3576-86.

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