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Natural Health Products and Drug Disposition

Natural Health Products and Drug Disposition. Brian C. Foster, Ph.D. Office of Science and Centre for Research in Biopharmaceuticals, University of Ottawa Society of Toxicology of Canada December 7, 2000. Natural Health Products. Confusion of Terms and Sources

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Natural Health Products and Drug Disposition

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  1. Natural Health Products and Drug Disposition Brian C. Foster, Ph.D. Office of Science and Centre for Research in Biopharmaceuticals, University of Ottawa Society of Toxicology of Canada December 7, 2000

  2. 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.

  3. Active Compound Classes • Carotenoids • Monoterpenes • Organosulfur compounds • Phenolics - polyphenols • Polypyrroles • Tocopherols - tocotrienols • Triterpenes, etc

  4. Use of Natural Products • Not a new phenomenon • About 250,000 species of flowering plants • Estimated that 25-50% have been used • WHO estimates use at 80% • ACNielson/NDMAC HealthVision • 24% reported use of herbal products • gender and age differences

  5. Grapefruit 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

  6. Soybeans • Phytoestrogens occur naturally in soybean and other plant products (eg. chick peas, lentils and lima beans) • High levels found in vegetarians • Five varieties had strong activity against 2C9, 2C19, 2D6 and 3A4.

  7. Biomarkers - CYP3A4 In vitro Inhibition

  8. Tinctures - CYP3A4 In vitro Inhibition

  9. Chinese Herbal Products - Powders

  10. Milk Thistle • Strong in vitro activity against P450 isoforms, Pgp, UDPglucuronosyl transferase • Flavanolignans – silybin, isosilybine, silycristine, silydianine, taxifoline • Silybin hemisynthetic derivatives have high in vitro Pgp affinity

  11. Quinine • 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

  12. St. 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.

  13. Garlic Case StudyChoudri 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

  14. The Question When is a clinical manifestation not a manifestation of disease but a drug induced side effect?

  15. Garlic - solvent extracts against CYP3A4

  16. Fresh Garlic

  17. Garlic Natural Health Products

  18. Garlic - Ritonavir Clinical Trial

  19. The Answer Interactions may be complex and time dependent! Need plasma levels in the patient population relative to actual use.

  20. Natural Product Variance • Climatic (humidity, rain, temperature) • Fresh versus processed (harvest and storage conditions) • Misidentification - product substitutions (mandrake or snakeroot for ginseng) • Regional and seasonal effects • Varietal - genetic manipulation • Use - combinations, time, frequency and amount

  21. Some inter-relationships which may lead to clinically relevant 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

  22. Therapeutic Implications • increase or decrease the toxicity of conventional therapies • increase or decrease the efficacy of a drug - potential drug sparing (boosting) agents • adjuncts to conventional therapies • challenges with the natural products highlights need for sound medical research

  23. Collaborators • 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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