Natural Health Products and Drug Disposition

Health SantéCanada Canada

Natural Health Products and Natural Health Products and Drug DispositionDrug Disposition

Brian C. Foster, Ph.D.Brian C. Foster, Ph.D.

Office of Science and Centre for Research in Office of Science and Centre for Research in Biopharmaceuticals, University of OttawaBiopharmaceuticals, University of OttawaSociety of Toxicology of CanadaSociety of Toxicology of Canada

December 7, 2000December 7, 2000


Therapeutic Products ProgrammeProgramme des produits thérapeutiques

Natural Health Products

Confusion of Terms and Sources Animal, plant, microbe, mineral Alternative - Complementary medicines Herbal products/medicines Nutraceuticals (functional foods) Traditional medicines

Can be a medicine, health food product or raw ingredient.



Active Compound ClassesActive Compound Classes

CarotenoidsCarotenoids MonoterpenesMonoterpenes Organosulfur compoundsOrganosulfur compounds Phenolics - polyphenolsPhenolics - polyphenols PolypyrrolesPolypyrroles Tocopherols - tocotrienolsTocopherols - tocotrienols Triterpenes, etcTriterpenes, etc



Use of Natural ProductsUse of Natural Products

Not a new phenomenonNot a new phenomenon About 250,000 species of flowering plantsAbout 250,000 species of flowering plants

Estimated that 25-50% have been usedEstimated that 25-50% have been used WHO estimates use at 80%WHO estimates use at 80% ACNielson/NDMAC HealthACNielson/NDMAC HealthVisionVision

24% reported use of herbal products24% reported use of herbal productsgender and age differencesgender and age differences



Grapefruit and Seville OrangeGrapefruit and Seville Orange

Increase serum levels Antihistamines, calcium

channel blockers, cyclosporine

Furanocoumarins - FC726, bergamottin, bergapten, dihydroxybergamottin, bergaptol

Flavonoids – chrysin, naringenin, quercetin

Quercetin – 0.1 mg/kg<; 1.0 mg/kg> vincristine



SoybeansSoybeans

Phytoestrogens occur Phytoestrogens occur naturally in soybean and naturally in soybean and other plant products (eg. other plant products (eg. chick peas, lentils and chick peas, lentils and lima beans)lima beans)

High levels found in High levels found in vegetariansvegetarians

Five varieties had strong Five varieties had strong activity against 2C9, activity against 2C9, 2C19, 2D6 and 3A4.2C19, 2D6 and 3A4.



Biomarkers - CYP3A4 Biomarkers - CYP3A4 In vitroIn vitro Inhibition Inhibition

Compound IC50 Concentration (mM)

R2 RankedInhibition(Potential Source)

Ketoconazole (antifungal drug)

7.18x10-4

(7.47, 6.97)x10-4 0.946 1

Dillapiol (dill, pepper)

1.67x10-2

(1.07, 2.35)x10-2 0.937 2

Hypericin (St. John’s wort)

0.33 (0.46, 0.28) 0.751 3

Naringenin (grapefruit, wild cherry)

0.42 (0.43, 0.40) 0.950 4

Parthenolide (feverfew)

1.36 (1.87, 1.09) 0.872 5

Berberine (goldenseal)

5.72 (7.59, 4.53) 0.963 6

Dihydrokaempferol(wild cherry)

5.79 (7.23, 4.86) 0.960 7

Compound IC50 Concentration (mM)

R2 RankedInhibition(Potential Source)

Ketoconazole (antifungal drug)

7.18x10-4

(7.47, 6.97)x10-4 0.946 1

Dillapiol (dill, pepper)

1.67x10-2

(1.07, 2.35)x10-2 0.937 2

Hypericin (St. John’s wort)

0.33 (0.46, 0.28) 0.751 3

Naringenin (grapefruit, wild cherry)

0.42 (0.43, 0.40) 0.950 4

Parthenolide (feverfew)

1.36 (1.87, 1.09) 0.872 5

Berberine (goldenseal)

5.72 (7.59, 4.53) 0.963 6

Dihydrokaempferol(wild cherry)

5.79 (7.23, 4.86) 0.960 7



Tinctures - CYP3A4 Tinctures - CYP3A4 In vitroIn vitro Inhibition Inhibition

TinctureIC50 Concentration (% Full Strength)

R2 RankedInhibition

Goldenseal 0.03 (0.04, 0.02) 0.824 1

St. John’s Wort 0.04 (0.05, 0.03) 0.829 2

Cat’s Claw 0.79 (1.56, 0.66) 0.962 3

Red Clover 1.05 (1.80, 0.72) 0.900 4

Echinacea angustifolia 1.05 (2.19, 0.64) 0.888 4

Chamomile 1.48 (1.97, 1.16) 0.972 5

Licorice 1.83 (4.29, 1.11) 0.883 6

Echinacea purpurea (roots) 3.99 (7.74, 2.39) 0.944 7



Chinese Herbal Products - PowdersChinese Herbal Products - Powders

Product 2C9 2C19 2D6 3A4

Antaisu 0.0 ± 13.36 12.7 ± 9.36 6.3 ± 1.14 20.8 ± 5.74

Banlangen(cube)

37.1 ± 3.79 16.0 ± 9.57 28.8 ± 1.19 33.8 ± 1.27

Banlangen (powder) 0.0 ± 34.50 0.6 ± 7.93 7.8 ± 0.56 27.0 ± 1.88

De le ke chuan kang 85.3 ± 3.76 87.7 ± 14.58 45.2 ± 1.18 94.5 ± 1.38

Huo xiang zheng qi pian 82.2 ± 8.14 87.2 ± 3.54 80.3 ± 0.40 58.8 ± 1.06

Rensheng dao 90.9 ± 30.2 83.4 ± 7.27 33.1 ± 4.21 97.1 ± 0.74

Xiangsha jian piwan 42.6 ± 23.11 14.4 ± 1.90 42.4 ± 0.78 26.9 ± 0.31

Zhi ke Wan 67.4 ± 11.00 75.7 ± 0.30 41.5 ± 1.46 11.2 ± 2.72

"Stop coughing" 55.1 ± 5.98 67.4 ± 6.97 46.6 ± 2.03 92.8 ± 1.58



Milk Milk ThistleThistle

Strong Strong in vitroin vitro activity activity against P450 isoforms, against P450 isoforms, Pgp, UDPglucuronosyl Pgp, UDPglucuronosyl transferasetransferase

Flavanolignans – silybin, Flavanolignans – silybin, isosilybine, silycristine, isosilybine, silycristine, silydianine, taxifolinesilydianine, taxifoline

Silybin hemisynthetic Silybin hemisynthetic derivatives have high derivatives have high in in vitrovitro Pgp affinity Pgp affinity



QuinineQuinine

HIV/AIDS community to reduce muscle cramps

Present in tonic water 52.7 - 95.7 µg/ml 250 ml contains 13.2 - 24

mg

CYP3A4 substrate: ~5x more active than

quinine



St. John’s wortSt. John’s wort

43 subjects, 475 ± 360 mg/day (300 - 1200 mg), 7.3 ± 10.1 wk (1d - 5y), 47% ADE

7 subjects, q8h, 300 mg 4d, unlikely to affect 2D6-3A4

2 subjects acute cardiac rejection on SJW 3 wk

8 subjects, q8h, 800 mg IND 1-2d, 300 mg 3-17d, IND added d16, test d17

Piscitelli et. al. Lancet, 355:547, 2000.



Garlic Case StudyGarlic Case StudyChoudri et. al. 1998Choudri et. al. 1998

Serious adverse drug events in two AIDS patients taking ritonavir 4 capsules odourless

garlic daily (2x daily dose)

6-7 cloves of raw garlic ADE consistent with

disease, RIT and garlic



The QuestionThe Question

When is a clinical manifestation not a manifestation of disease but

a drug induced side effect?



Garlic - solvent extracts against CYP3A4Garlic - solvent extracts against CYP3A4

Hexane Chloroform Methylene Ethyl MethanolChloride Acetate

Aged 37.2 ± 59.6 67.8 ± 31.8 67.9 ± 5.2 83.2 ± 2.8 54.0 ± 7.3Common 135.8 ± 36.1 92.9 ± 23.3 65.0 ± 8.0 72.9 ± 5.0 58.6 ± 14.3Elephant 87.0 ± 6.2 72.0 ± 24.8 93.4 ± 5.0 93.3 ± 3.3 92.0 ± 5.6Chinese 91.3 ± 9.8 116.1 ± 18.9 90.7 ± 5.2 85.1 ± 5.8 48.2 ± 9.0

Fresh GarlicFresh Garlic

Cytochrome P450

*2C9*1 *2C9*2 *2C19 *3A4 *2D6

Flu

ore

sen

ce C

ou

nts

0

1000

2000

3000

4000

5000

6000 ControlRegular garlicElephant garlicChinese garlic



Garlic Natural Health ProductsGarlic Natural Health Products

Product 2C9 2C19 2D6 3A4

Odourless1 33.5 ± 3.64 30.0 ± 5.26 4.8 ± 2.01 53.8 ± 2.152 21.4 ± 5.24 28.5 ± 4.95 1.8 ± 2.71 39.1 ± 3.313 23.4 ± 2.60 36.6 ± 6.19 5.0 ± 0.63 30.8 ± 4.424 32.4 ± 3.50 25.6 ± 3.05 7.5 ± 2.21 42.5 ± 3.845 31.5 ± 5.68 21.0 ± 11.47 6.9 ± 2.75 46.3 ± 4.196 4.8 ± 2.17 53.2 ± 5.25 4.4 ± 1.43 55.7 ± 5.85

Oil7 22.2 ± 1.79 0.0 ± 5.09 4.9 ± 1.05 31.3 ± 2.138 1.4 ± 2.43 0.0 ± 7.71 5.0 ± 0.62 17.4 ± 1.47

Tablet9 0.0 ± 9.07 5.1 ± 4.13 6.5 ± 0.35 95.8 ± 0.81

Capsule10 31.3 ± 2.83 0.0 ± 14.64 8.7 ± 0.93 44.2 ± 3.62



Garlic - Ritonavir Clinical TrialGarlic - Ritonavir Clinical Trial

0 3 6 9 12 15 18 21 24 27 30

Time after dose (h)

100

1000

10000

Pla

sma

rito

na

vir

co

nc

entr

atio

n (

ng

/mL

)Effect of garlic (10 mg bid x 4 days) on

Ritonavir (400 mg single dose) pharmacokinetics (mean ± SD)

Ritonavir alone

Ritonavir + Garlic



The AnswerThe Answer

Interactions may be complex and time dependent!

Need plasma levels in the patient population relative to actual use.



Natural Product VarianceNatural Product Variance

Climatic (humidity, rain, temperature)Climatic (humidity, rain, temperature) Fresh versus processed (harvest and storage Fresh versus processed (harvest and storage

conditions)conditions) Misidentification - product substitutions Misidentification - product substitutions

(mandrake or snakeroot for ginseng)(mandrake or snakeroot for ginseng) Regional and seasonal effectsRegional and seasonal effects Varietal - genetic manipulationVarietal - genetic manipulation Use - combinations, time, frequency and amountUse - combinations, time, frequency and amount



Some inter-relationships which may lead to Some inter-relationships which may lead to clinically relevantclinically relevant drug interactions drug interactions

Clinical status - age, disease state, pregnancy, physiology

Environment - diet, nutrition, exposure (single or repeated dosing)

Genetics - metabolism and transport components

Pre-systemic and systemic



Therapeutic ImplicationsTherapeutic Implications

increase or decrease the toxicity of increase or decrease the toxicity of conventional therapies conventional therapies

increase or decrease the efficacy of a drugincrease or decrease the efficacy of a drug-- potential drug sparing (boosting) potential drug sparing (boosting)

agentsagents adjuncts to conventional therapiesadjuncts to conventional therapies challenges with the natural products challenges with the natural products

highlights need for sound medical researchhighlights need for sound medical research



CollaboratorsCollaborators

Humayoun Akhtar - Agri-Food and Agriculture Canada John (Thor) Arnason - Ottawa Jason Budzinski - Ottawa Dennis Bulman - Ottawa Hospital Research Institute Bob Drobitch - Dalhousie Keith Gallicano - Axelson Biopharma Research, Vancouver Tony Krantis - Ottawa Richard Lalonde - Montreal Vance Trudeau - Ottawa Raymond Viola - Ottawa

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Natural Health Products and Drug Disposition