Herb-Drug Interactions

Prepared by Shaza AlAl-Massarani Supervised by Dr. Taghreed Abdou

1 PDF created with pdfFactory trial version www.pdffactory.com

Medicinal Use of Plants

q Plants have always provided an important source of medicines q Used by natives in folk medicine and later adopted by conventional western medicine as their efficacy was confirmed q A mistaken belief emerged that All that is natural is superior to all that is synthetic q Large variety of herbal preparations and products is used by people all over the world q The selection of a particular herb reflects the diverse ethnic backgrounds of the users

Ioannides, 2002, Xenobiotica 32: 451-478

Statistics: Dietary Supplement Education Alliance Survey (July 2001)

59% take dietary supplements on a regular basis 23% take herbal and specialty products (15% botanicals, 8% non botanical supplements) 95% indicate satisfaction; 75% very satisfied or extremely satisfied 49% only consult with health care providers about taking supplements

o 30% of adults in developed nations use CAM o 80% of the population in many developing countries use herbal medicines

Eisenberg et al, 2001, Ann Intern Med 135: 344-351

2 PDF created with pdfFactory trial version www.pdffactory.com

Problems Associated With the Use of Herbal Remedies

Safe, natural but
Scarcity of established regulatory standards for herbal drugs The Complex nature of herbal drugs Mixtures of multiple herbs Used parts Seasonality, growing conditions Manufacturing process Lack of accurate information sources Toxicity and adverse effects of herbal drugs

The interaction between complementary herbal drugs and conventional medicines

Noonana and Noonan, 2006, Toxicology 221: 4-8.

Mechanisms for Herbal Interactions with Prescription Drugs

3 PDF created with pdfFactory trial version www.pdffactory.com

qA herb-Drug Interaction
Any pharmacological modification caused by a herbal substance(s) to another prescription medication (diagnostic, therapeutic or other action of a drug) in or on the body

q A herb might mimic, or the effects of co-administered

drugs q Consequences can be beneficial, undesirable or harmful effects

Brazier and Levine, 2003. Am J Ther 10: 163-169.

Xenobiotic Metabolism

4 PDF created with pdfFactory trial version www.pdffactory.com

Phases of Xenobiotic Metabolism

Phase I (oxidation)
Cytochrome P450

Phase II (conjugation) (UGTs)

R= any xenobiotic (herb, medicine, food) Y= moiety such as glucuronic acid

Types of Herb-Drug Interactions

Alteration of absorption, distribution, metabolism or elimination

Pharmacokinetic (PK) interactions Phase I pathway (CYPs) Phase II pathway (UGTs) Role of efflex proteins & transporters

Pharmacodynamic (PD) interactions pharmacological function

Other influencing factors Interference with absorption Therapeutic index Individual differences Effect of multiple medications
Chavez et al, 2006, Life science 78: 2146-2157

5 PDF created with pdfFactory trial version www.pdffactory.com

Relative isozymes RelativeLevels Levelsof ofP450 P450 Isozymes in human liver in Human Liver

28%

30%

7% 13% 20% 2%

CYP 3A4 CYP2C CYP2D6 CYP1A2 CYP2E1 Other

CYP3A4: responsible for the metabolism of more than 50-70% of all prescribed drugs 82% of Drugs that Interact With Herbs Are Substrates For Cytochromes P450s
Kaminsky and Zhang, 1997, Pharmacol Ther 73: 67-74

Herbs # CYP450 System

A herb can be an inducer of a CYP isoform
St. John's Wort Tea Cruciferous vegetables Common valerian Ginkgo

A herb can be an inhibitor of a CYP isoform

Horse chestnut Echinacea purpurea Common sage Grapefruit juice Red clover blossom Kava-kava root Feverfew herb Devil's claw root Peppermint oil Milk thistle (silymarin)

Results: Increase / Decrease in the rate of metabolism of enzyme substrates

Block and Gyllenhaal, 2002, Integrative Cancer Therapies 1: 83-89

6 PDF created with pdfFactory trial version www.pdffactory.com

Drugs # Herbs # CYPs

These drugs are substrates for CYPs enzymes and their therapeutic concentrations can be affected by concomitant use of previously mentioned herbs
Drug Warfarin/ Phenprocoumon

CYP 1A2, 2C9, 1A2 3A4 3A4 3A4 3A4 2C9 3A4 3A4 3A4 3A4

Simvastatin Cyclosporin Oral contraceptives Indinavir Omeprazole Amitriptyline Imitinab Saquinavir Midazolam

Herbs # Phase II Enz. (UGTs)

Phase II Enz. (conjugation) UGTs metabolize a broad range of endogenous and exogenous substances Milk thistle Garlic

Radominska-Pandya et al, 1999

7 PDF created with pdfFactory trial version www.pdffactory.com

Herbs # P-Glycoproteins
P-glycoproteins
Act as pump to remove drugs from cells against a steep concentration gradient. P-GP plays important roles in the absorption, distribution or elimination of drugs from various tissues

Curcumin Ginsenosides Piperine Sylimarin Catechins & flavonoids (quercetin) 29% of the drugs that interact with herbs are substrates for P-glycoprotein (P-gp)

Pizzagalli et al, 2001, Gastroenterology 120: 525-533

Drugs # Herbs # P-GPs

Digoxin Warfarin/Phenprocoumon Cyclosporine Fexofenadine Indinavir Simvastatin Irinitecan

Faber et al, 2003, Advanced Drug Delivery Reviews 55: 107-124

8 PDF created with pdfFactory trial version www.pdffactory.com

Herbal laxatives
Decrease blood levels of drugs by shortening gastrointestinal transit time Increase potassium loss Common herbal laxatives: Aloe, cascara, rhubarb, senna

Abebe W, 2003., J Dental Hygiene 77:37-46

Popular Herbal Products and Their Interactions with Therapeutic Drugs

9 PDF created with pdfFactory trial version www.pdffactory.com

Herb-Drug Interactions
10 Top selling herbs (2006)
Courtesy of Information Resources, Inc., Chicago, IL

Ginkgo (G. biloba) Phytoestrogens / Isoflavaones Echinacea (E. purpurea) Ginseng (Panax ginseng) St. Johns Wort (H. perforatum ) Garlic (Allium sativum ) Saw Palmetto (Serenoa serrulata) Valerian (V. officinalis) Milk thistle (Silybum marianum) Kava (Piper methysticum)

HerbalGram 2005;66:63

St Johns Wort

10 PDF created with pdfFactory trial version www.pdffactory.com

Hypericum perforatum L. (Hypericaceae) St Johns Wart

Extract of the dried flowering portion Widely used for depression SJW same as Imipramine with fewer
adverse effects in multicentered German study in patients with mild to moderate depression

Complex mixture of > two dozen chemicals

Chemical Structure of Major Components of St. John's Wort

Hyperforin Hypericin Pseudohypericin Adhyperforin Biapigenin Quercetin Quercitrin Isoquercitrin Hyperoside Rutin

11 PDF created with pdfFactory trial version www.pdffactory.com

Hypericin and Hyperforin in Eight Brands of St. Johns Wort

ProductHyperifin PNC Brite-Life ShopKo Shurfine YourLife Natures Balance Natrol hypericin (%) 0.29 0.12 0.22 0.26 0.17 0.28 0.03 0.25 hyperforin (%)* 1.89 0.20 1.16 0.05 0.29 0.19 0.01 0.48

Commercial preparations are often standardized to 0.3 mg per capsule hypericin & 1% hyperforin

De Los Reyes and Koda, Am J Health-syst Pharm 59:545-547.2002

St. Johns Wort & Interactions

In 2000, FDA issued a public health advisory informing the public of the risk of drug-herb interactions with St. Johns Wort
Most commonly used herbal product, which causes severe Herb-drug interactions

http: www.fda.gov/cder/drug/advisory/stjwort.htm.

12 PDF created with pdfFactory trial version www.pdffactory.com

St. Johns Wort & Interactions

PD interactions
With other antidepressants SJW has both SSRI and MAO inhibiting activity Restlessness, nausea, vomiting, tachycardia, hallucinations etc. Case reports with: Buspirone Loperamil Paroxetine Sertraline Venlafaxine

Venkatakrishnan et al, 1999, Life science 78:11051115

St. Johns Wort & Interactions

Case reports suggesting PK interactions
(Most important of SWJ interactions)

Lab studies indicate PK interactions: CYP450: 3A4, P-gp Short-term inhibition Long-term induction (most important clinically) Reduces various drugs to subtherapeutic levels

Hennessy et al, 2002, Br J Clin Pharmacol 53: 75-82

13 PDF created with pdfFactory trial version www.pdffactory.com

St. Johns Wort Induction of CYP3A4 Expression

CYP- 3A4 expression

Moore,L.B. et al PNAS, 97: 7500-7502,200

St. Johns Wort & Interactions

Study: 2 case reports case 1: 61 yr had transplant 11mos earlier; cyclosporin, azathioprine, steroids for 11 mos. Unexplained heart failure noted after SJW started. case 2: 63 yr had transplant 20mos earlier: same senario as case 1.

Ruschitzka et al. Lancet 355:548-549,2000

14 PDF created with pdfFactory trial version www.pdffactory.com

Effect of St Johns Wort on Plasma Conc. Of Alprzolam

Markowitz et al. JAMA 290:1500,2003 n=12 14d of SJW

St. Johns Wort & Interactions

Summary of SJW Interactions Drug
HIV protease inhibitors (Nelfinavir, ritonavor, saquinavir) Warfarin Cyclosporin Oral contraceptives Digoxin Theophylline

CYP
3A4 induct.

Effect

Management
Stop and measure viral load Stop and adjust warfarin dose Stop and adjust cyclosporine dose Stop and use alternate birth control Stop and adjust digoxin dose Stop and adjust theophylline dose Stop

2C9 induct. P-glycoprotein induct. Induce 3A4 P-hlycoprotein induct. 1A2 induct.

Triptans (sumatriptan)

Increase serotonin

Henderson et al. Br J Clin Pharmacol 2002;54:349-346

15 PDF created with pdfFactory trial version www.pdffactory.com

2. Echinacea

E. angustifolia, E. pallida, E. purpurea (Compositae)

Alcoholic extract of the root of E. angustifolia The juice from the fresh aerial parts of E. purpurea Immunostimulant The German Commission E monograph Approved the oral use of E. purpurea herb for treatment of colds, RTI, and UTI, Topically: poorly healing wounds
Constituents Alkamides (phagocytosis stimulatory effect) Vol. oils Pyrrolizidene alkaloids Ferulic acid derivatives Complex polysaccharides
E. pallida roots
PDR for Herbal Medicines, 1998

E. angustifolia

16 PDF created with pdfFactory trial version www.pdffactory.com

COOCH3
O HO OH OH

OH
HO

H O O O

O OH H O

OH

Tussilagine
HO HO COOH

Cichoric acid
GLo-O O HO O Rha-O
O

H2C

O O OH

HO O OH

OH

HO OH

Cholorogenic acid

Echinacoside

OH

Some of the hydrophilic components of E. purpurea extract

An alkamid
Major lipophilic constituents

Humulene

Caryophyllene

Some volatile constituents of Echinacea roots

Echinacea & Interactions

The German Commission E monograph, recommends that Echinacea not be taken by patients receiving
Immunosuppressive medications Autoimmune conditions HIV infection > 8 weeks? Hepatotoxic drugs (Methotrexate, anabolic steroids)

17 PDF created with pdfFactory trial version www.pdffactory.com

Echinacea & Interactions

PK: (In vitro studies)
Inhibits 1A2 May inhibit intestinal 3A4 but induce

hepatic
Clinical significance unclear

Gorski et al, 2004, Clinical Pharm. Therap. 75: 89-100.

Gingko biloba L.

18 PDF created with pdfFactory trial version www.pdffactory.com

Gingko biloba L. (Ginkogoaceae) Gingko

It is among the most sold medicinal plants in the world (sales > 1 billion dollars) Special standardized extracts from the leaves EGb 761 is registered in Germany and other countries for the treatment of dementia disorders & cerebral circulatory disturbances Standardized leaves constituents
Terpene trilactones (ginkgolides & bilobalides) Flavonol glycosides Biflavones and proanthocyanidins

Kanowski et al, 1996, Pharmacopsychiatry 29: 47-56

Bilobalide

OH OH

G-A: G-B: G-C: G-J: G-M:

OH

Ginkgolide R1= OH, R2= R3=H R1= R2=OH, R3=H R1= R2= R3= OH R1= R3=OH, R2=H R1=H, R2= R3=OH

HO

R OH OH OH

COOH

OH

HO

HO HO

O R

OH OH

R
HO R

Procyanidin Pridelphinidin

R=H R=OH Ginkgolic acid

Bilobols
R= alkyl chain

Ginkgol, R=C13H27

19 PDF created with pdfFactory trial version www.pdffactory.com

Gingko biloba & Interactions

Case reports of interactions (PD)
Ginkgo # Drug
Aspirin (1 week) Acetaminophen (2 mos) Warfarin Valproate Trazodone None (2 yrs)

Result of inter.
Hyphema (blood in eye) Bilateral subdural hematomas Intracerebral hemorrhage 2 cases of seizures reversed coma Subdural hemorrhage

Yin et al. Pharmacogenetics 2004;14:841-850 Meisel et al, 2003, Life science 78:2146-2157

Gingko biloba & Interactions

PK: Possible induction of CYP2C19 and CYP 3A4, but studies have conflicting results

Mary et al, 2005, Life science 78:2146-2157

20 PDF created with pdfFactory trial version www.pdffactory.com

Ginseng

Panax ginseng C.A, P. quinquefolium L., P. japonicus M. (Araliaceae)

Long-term traditional use for over 2000 yrs Approved by Commission E in 1981 as a tonic to counteract weakness and fatigue, a restorative for declining stamina and impaired concentration Some evidences for applications in geriatric patients (improved quality of life) and in diabetes Roots constituents Steroidal saponins > 30 ginsenosides, varying conc.
Lieberman, 2001, Clin Invest 102: 1016-1023

21 PDF created with pdfFactory trial version www.pdffactory.com

Chuang et al, 1995, Planta Med 61: 459-465.

Ginseng & Interactions

Case reports of interactions (PD)
Drug Loop diuretics Monoamine oxidase inhibitors Caffeine Insulin Estrogen hormone therapy Antipsychotic drugs Results Hypertension and edema Manic-like episodes, headache tremulousness Stimulant effect, headache Hypoglycemia Symptoms of estrogen excess or interference Neurotransmitter transport interfer

Vuksan et al, 2000, Arch Intern Med 160:1009-1013 ; Angell, 2003,

22 PDF created with pdfFactory trial version www.pdffactory.com

Warfarin # Ginseng
Probable interaction (PK) 47 yr old male on warfarin for 10 years with an INR of 3-4 Started ginseng (INR= 3.1) INR declined to 1.5 after 3 weeks on ginseng INR increased to 3.3 after stopping Ginseng causing CYP induction?

Janetzky and Morreale, Am J. Health-Syst Pharmacy 54:692-693,1997

Phytoestrogens Containing Herbs

23 PDF created with pdfFactory trial version www.pdffactory.com

Phytoestrogens Containing Herbs

Alfalfa ( Medicago sativa)

Red clover (Trifolium pratense) Dong quai (Angelica sinensis) Chaparral (Larrea tridentata)

Phytoestrogens Containing Herbs

Secondary plant metabolites with estrogenic properties found in Plants, fruits, vegetales & foodstuffs (e.g., cereal grains, soy milk) Classes Isoflavones in legumes (genistein and daidzein) Lignans in cereal brans, flax seeds (enterodiol and enterolactone) Coumestans in bean sprouts (coumestrol )
Soy bean

Sava et al, 1998, Proc Soc Exp Biol 217: 369-378

24 PDF created with pdfFactory trial version www.pdffactory.com

Compounds with phytoestrogenic properties

HO O

HO

HO

O OH

O OH

OH

O OH

O O

Daidzeien

Genistein Coumestrol
H3CO

H3CO

OH OH
HO

HO

O
OH OH
OH OH

Enterodiol

enterolactone

Coumestan

Phytoestrogens Containing Herbs

Asian cultures: Long consumption of soy associated with

lower rates of breast, endometrial and prostate cancers Animal studies: Soy and some soy isoflavones decrease prostate cancer and breast cancer growth Increased phytoestrogen ingestion may decrease hot flashes, osteoporosis and other postmenopausal symptoms Soy-Cardiovascular Benefits Favorable effects on cholesterol balance; heart healthy

Ratna, 2002, Life Sci 71: 865-877

25 PDF created with pdfFactory trial version www.pdffactory.com

Phytoestrogens Containing Herbs & Interactions

But
In vitro and animal studies: estrogen agonist effects of isoflavones might increase the growth of breast cancer cells Genistein enhances effect of Adriamycin on breast cancer cells but blocks inhibitory effect of Tamoxifen In virto studies: CYP3A4 activation by soy extracts (no clinical support) Abs. of levothyroxine

Bell and Ovalle, 2001, Endocrin Pract 7: 193-194. Messina, 2006, J PeriAnesthesia Nursing 21: 268-278.

Garlic

26 PDF created with pdfFactory trial version www.pdffactory.com

Allium sativum L., (Liliaceae) Garlic

The herb of the year (2004) by the Herb Society

of America Medicinal purposes Composed of dried garlic powder standardized for allicin content Used as: Antiplatelet Antioxidant Fibrinolytic effects Antihypercholesterolemic Treatment of common cold Red. Cancer risk

Valli and Giardina, 2002, J.Am. College of Cardiology 39: 1083-1095.

Garlic active constituents (bulb)

Organosulfur Glutamyl peptides Allylcysteine sulfoxides (alliin) Methyl allyl trisulfide Diallyl trisulfide Diallyl disulfide Ajoene Trace minerals (germanium & selenium)

27 PDF created with pdfFactory trial version www.pdffactory.com

Garlic & interactions

Garlic & CYPs/P-gp Studies suggest that garlic can act as an enzyme inhibitor during acute dosing and an enzyme inducer during chronic dosing Garlic & phase II enzymes Hepatic phase II enzymes GST and QR; were induced strongly by the trisulfide (dose:10 mol/kg) and weakly by the disulfide, but not by diallyl sulfide

Fukao et al, 2004, Bio Factors 21: 171-174

Garlic & interactions

Case reports of interactions
Drug # Garlic Result of # Elevated/ dec. levels of the drug Elevated levels of the drug Increased INR

Protease inhibitors PK Cyp 3A4 & P-gp (anti HIV) Acetaminophen/ch lorzoxazone Anticoagulants/ antiplatelets (warfarin) Hypoglycemic agents PK CYP2E1 inhibition PD additive anticoagulant effect PD hypoglycemic effect

Fall in glucose levels

Hsu et al, 2007, Clin Pharmacokinet 35: 275-291

28 PDF created with pdfFactory trial version www.pdffactory.com

Questions remaining
Product selection: Which product? Tincture? Tablets? How best to use this herb given that there are drug interaction problems

Multiple potential inter. with oncology drugs

Safety concern: Unclear clinical significance? Hepatotoxicity?

Approaches to Evaluate and Minimize Toxic Herb-drug Interactions in the Drug Development Process

29 PDF created with pdfFactory trial version www.pdffactory.com

Approaches to Evaluate and Minimize Toxic Herb-drug Interactions

Predicting a drugs potential for interaction with herbal medicines The use of in vitro and in vivo models
(liver microsomes, cytosols and homogenates) To study

CYPs, Phase II enzymes, P-gp and their interactions with xenobiotics, including herbs

Ekins and Wrighton, 2001, Pharmacol Toxicol. 45: 65-69

Approaches to Evaluate and Minimize Toxic Herb-drug Interactions

Regulatory measures to minimize herb- drug interactions The need for surveillance system & clinical trials to prove the safety and efficacy of this medicine Propagation of medicinal plants (genetically improve the reliability and quality of its products) Continuing education programs Increase the awareness to quality assurance problems (mislabeling, adulteration or contamination) Patients on complicated medical regimens should avoid herbs and supplements unless carefully screened/supervised Package inserts

30 PDF created with pdfFactory trial version www.pdffactory.com

31 PDF created with pdfFactory trial version www.pdffactory.com