Drug Interaction of Herbal and Western Medicines

1. Drug Interaction of Herbal and Western Medicines 胡幼圃 教授兼主任 Prof. Oliver Yoa-Pu Hu, Ph.D. Dean Research, Development and Continuing Education National Defense Medical Center Taipei, Taiwan, R.O.C. EHFG 5-8, Oct. 2005

2. Outline • Current Status of Herbal or Traditional Medicines in Eastern and Western World • Adverse Events and Drug-Interaction Caused by Herbal or Traditional Medicines • Evidences Based Drug-Interaction Caused by Herbal or Traditional Medicines • Conclusions and Suggestions EHFG 5-8, Oct. 2005

3. Current Status of Herbal or Traditional Medicines in Eastern and Western World EHFG 5-8, Oct. 2005

4. Insurance Paid for Herbal Medicines • German health insurance paid $283 million in reimbursements for prescribed ginkgo, St. John’s wort, mistletoe, saw palmetto, ivy, hawthorn, stinging nettle root, myrtol, phytosterols, and cucurbita in 2003. • French health insurance paid $91 million in partial reimbursements for ginkgo, saw palmetto, and pygeum prescriptions with a total value of $196 million in 2002. NEJM352:12, 2005 EHFG 5-8, Oct. 2005

5. European Market for Over-The-Counter Herbal Medicines in 2003 Distribution of the $4.96 Billion European Market for Over-the-Counter Herbal Medicines in 2003. *Taiwan Herbal Medicines market was 4.0 billion in 2002 NEJM352:12, 2005 EHFG 5-8, Oct. 2005

6. Herbal Medicines in US • In a 1990 survey of 1,539 adults, 33.8% of respondents used herbal medicines or nutritional supplements. • By 1997, the number had increased to 42.1%, with most people paying the cost out-of-pocket. • Approximately 40% of patients who use alternative therapies do not disclose this information to their doctor. AM J Ophthalmol138:639, 2004 EHFG 5-8, Oct. 2005

7. Adverse Events and Drug-Interaction Caused by Herbal or Traditional Medicines EHFG 5-8, Oct. 2005

8. Effect of Various CYP Isoforms by Herbal Constituents (I) (from Zizyphi fructus) CME = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = Primary Hepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

9. Effect of Various CYP Isoforms by Herbal Constituents (II) CME = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = Primary Hepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

10. Effect of Various CYP Isoforms by Herbal Constituents (III) CME = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = Primary Hepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort. Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

11. Known Pharmacokinetic Herb-Drug Interactions (I) Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

12. Known Pharmacokinetic Herb-Drug Interactions (II) Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

13. Potential Interactions between Herbs and Conventional Drugs (I) NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

14. Potential Interactions between Herbs and Conventional Drugs (II) NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

15. Potential Interactions between Herbs and Conventional Drugs (III) NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

16. Evidence Based Drug-Interaction Caused by Herbal or Traditional Medicines and Food EHFG 5-8, Oct. 2005

17. Simvastatin • HMG-CoA reductase inhibitor • As a substrate for both CYP3A4 and P-gp • Bioavailability < 5% EHFG 5-8, Oct. 2005

18. In Vitro Inhibiting CYP3A4 in Liver Microsomes with Herbal and Food Constituents (PC: ketoconazole) EHFG 5-8, Oct. 2005

19. Effect of HUCHE015 on Total Simvastatin Absorption on Female SD Rats by Oral *12.3 g of green-tea leaf contain 20 mg of HUCHE015 EHFG 5-8, Oct. 2005

20. PK Parameters of Simvastatic Acid of Female SD Rats after Oral SimvastatinSimvastatin 50 mg/kg in DMSO and HUCHE015 20 mg/kg in DMSO *12.3 g of green-tea leaf contain 20 mg of HUCHE015 EHFG 5-8, Oct. 2005

21. Fluvastatin • HMG-CoA reductase inhibitor • Specifically and extensively metabolized by CYP2C9 • Oral bioavailability: 20-30% EHFG 5-8, Oct. 2005

22. Fluvastatin in SD Rats after Orally Administered Fluvastatin with or without Herbal Constituents *The herbal constituents is HUCHE070 that is very rich in Eupatorium odoratum. The dose is 9.3 mg/kg EHFG 5-8, Oct. 2005

23. Fluvastatin PK Parameters in SD Rats after Orally Administered Fluvastatin with or without Herbal Constituents EHFG 5-8, Oct. 2005

24. Nalbuphine • Narcotic analgesics • k-agonist, m-antagonist • Advantage: low tolerance、 addiction、 and respiratory depression • Drawback: short duration • Mainly Metabolized by UGT2B7 • Oral bioavailability less than 5% EHFG 5-8, Oct. 2005

25. Nalbuphine in SD Rats after Oral Nalbuphine with or without Herbal Constituents *The HUCHE035 is very rich in Artemisia capillaris and the dose is 4.5 mg/kg. EHFG 5-8, Oct. 2005

26. PK Parameters for SD Rats after Oral Nalbuphine with or without Herbal Constituents EHFG 5-8, Oct. 2005

27. Conclusions and Suggestions (I) • Evidences from in vitro and in vivo studies has indicated that the constituents of herbal preparation, even food, interact with various drug metabolic enzymes extensively. • High throughput screening assays combine with in vivo or clinical study will be a useful strategy to examine the herb-drug interactions EHFG 5-8, Oct. 2005

28. Conclusions and Suggestions (II) • Medical and pharmaceutical communities had been slow to respond to this important issue • Government, industry and medical societies should vigorously examine the possible drug interaction with the most commonly used herbal drugs • Drug Insert should clearly indicate the clinically significant drug interaction with commonly used herbs, dietary supplements, healthy food and traditional medicines EHFG 5-8, Oct. 2005

29. Thanks for your attention EHFG 5-8, Oct. 2005

30. Problems Caused from Herbal Medicines • Potential adulterants and contaminations that can affect the quality of herbal remedies • Plants containing belladonna or pyrrolizidine alkaloids, microorganisms, aflatoxins, bacterial endotoxin, pesticides, fumigation agents, toxic metals and Drugs • Potential adverse effects of herbal remedies and their major constituents • Cardiotoxicity: aconire root ruber • Hepatoxicity: certain herbs rich in anthranoids and protoberberine alkaloids, green-tea leaf • Neurotoxicity or convulsions: Kava rhizome • Renal toxicity: -Aescin (saponin mixture from horse-chestnut seed) NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

31. EHFG 5-8, Oct. 2005

32. Potential Adulterants and Contaminants that Can Affect the Quality of Herbal Remedies NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

33. Potential Adverse Effects of Herbal Remedies and Their Major Constituents NEJM347:2046, 2002 EHFG 5-8, Oct. 2005

34. Effects of St. John’s Wort Constituents on the Activity of Various CYPs Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005

35. Induction of Various CYP Isoforms by Herbal Constituents (I) Drug Metabolism Reviews35:35, 2003 EHFG 5-8, Oct. 2005