Natural Health Products and Drug Disposition
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Transcript of 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
Health SantéCanada Canada
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.
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
Active Compound ClassesActive Compound Classes
CarotenoidsCarotenoids MonoterpenesMonoterpenes Organosulfur compoundsOrganosulfur compounds Phenolics - polyphenolsPhenolics - polyphenols PolypyrrolesPolypyrroles Tocopherols - tocotrienolsTocopherols - tocotrienols Triterpenes, etcTriterpenes, etc
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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.
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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.
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
The QuestionThe Question
When is a clinical manifestation not a manifestation of disease but
a drug induced side effect?
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
The AnswerThe Answer
Interactions may be complex and time dependent!
Need plasma levels in the patient population relative to actual use.
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
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Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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
Health SantéCanada Canada
Therapeutic Products ProgrammeProgramme des produits thérapeutiques
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