1. EHFG 5-8, Oct. 20051 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.

2. 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

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

4. 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. NEJM 352:12, 2005

5. EHFG 5-8, Oct. 2005 5 European Market for Over-The- Counter Herbal Medicines in 2003 NEJM 352:12, 2005 *Taiwan Herbal Medicines market was 4.0 billion in 2002 Distribution of the $4.96 Billion European Market for Over-the-Counter Herbal Medicines in 2003.

6. 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 Ophthalmol 138:639, 2004

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

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

9. EHFG 5-8, Oct. 2005 9 Effect of Various CYP Isoforms by Herbal Constituents (II) Drug Metabolism Reviews 35:35, 2003 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.

10. EHFG 5-8, Oct. 2005 10 Effect of Various CYP Isoforms by Herbal Constituents (III) Drug Metabolism Reviews 35:35, 2003 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.

11. EHFG 5-8, Oct. 2005 11 Known Pharmacokinetic Herb-Drug Interactions (I) HerbInteraction DrugEffect PiperinePhenytoin, propranolol, theophylline, Curcumin (from Curcuma longa) Increase the plasma AUC and Cmax (human) Grape fruit juiceFelodipine, terfenadine, saquinavir, cyclosporine, midazolam, triazolam, verapamil, lovastatin, cisapride, astemizole Increase the oral bioavailability (human) Danshen (from the root of Salvia miltiorrhiza) R- and S- WarfarinIncrease the AUC and Cmax Decrease the clearance and apparent volume of distribution (rat) Drug Metabolism Reviews 35:35, 2003

12. EHFG 5-8, Oct. 2005 12 Known Pharmacokinetic Herb-Drug Interactions (II) HerbInteraction DrugEffect Dong quai (from Angelica dahurica) TolbutamideDecrease the elimination DiazepamIncrease the Cmax fourfold Khat (Catha edulis) AmpicillinReduce the bioavailability significantly GinsengAlcoholDecrease the blood concentration (human) Enhance plasma clearance LicoricePrednisoloneIncrease the AUC Xiao Chai Hu Tang PrednisoloneDecrease the AUC TolbutamideDecrease the plasma concentration Drug Metabolism Reviews 35:35, 2003

13. EHFG 5-8, Oct. 2005 13 Potential Interactions between Herbs and Conventional Drugs (I) NEJM 347:2046, 2002 Herb Conventional Drug Comments Ginkgo leaf Acetylsalicylic acid Rofecoxib Warfarin Trazodone Ginkgo combined with acetylsalicylic acid, rofecoxib, or warfarin has been associated with bleeding reactions. Coma was reported in a patient with Alzheimer’s disease who took ginkgo leaf with trazodone. Hawthorn leaf or flower Digitalis glycosides Since hawthorn may exert digitalis-like inotropic effects, it is prudent to monitor persons taking this herb in addition to digitalis glycosides closely.

14. EHFG 5-8, Oct. 2005 14 Potential Interactions between Herbs and Conventional Drugs (II) NEJM 347:2046, 2002 Herb Conventional Drug Comments St. John’s wort 5-Aminolevulinic acid Amitriptyline Cyclosporine Digoxin Indinavir Midazolam Nefazodone Nevirapine Oral contraceptives Paroxetine Phenprocoumon Sertraline Simvastatin Tacrolimus Theophylline Warfarin A phototoxic reaction occurred in a patient simultaneously exposed to 5-aminolevulinic acid and St. John’s wort; in clinical studies, pretreatment with St. John’s wort decreased the area under the curve for amitriptyline (and its active metabolite nortriptyline), digoxin, indinavir, midazolam, phenprocoumon, and the active metabolite of simvastatin (simvastatin hydroxy acid); case reports have associated St. John’s wort with reduced levels of cyclosporine (sometimes with transplant rejection), tacrolimus, and theophylline; with increased oral clearance of nevirapine; with intermenstrual bleeding or altered menstrual bleeding in users of oral contraceptives; and with reduced effects of phenprocoumon and warfarin; lethargy and grogginess were reported in a patient taking St. John’s wort and paroxetine, and the serotonin syndrome has been reported in users of nefazodone or sertraline (case reports); St. John’s wort alone has also been associated with serotonin syndrome– like events (case reports).

15. EHFG 5-8, Oct. 2005 15 Potential Interactions between Herbs and Conventional Drugs (III) NEJM 347:2046, 2002 Herb Conventional Drug Comments Garlic bulb Ritonavir Saquinavir Warfarin Gastrointestinal toxic effects in patients taking garlic and ritonavir. AUC for saquinavir decreased by 51 percent in patients taking garlic for 20 days; it returned to 65 percent of base line after a 10-day washout period. An increased clotting time in two patients taking warfarin and garlic. Kava rhizome Alprazolam Cimetidine Terazosin Lethargy and disorientation were reported in a patient receiving this triple-drug regimen.

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

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

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

19. 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

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

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

22. 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

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

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

25. 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.

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

27. 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

28. 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

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

30. 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) NEJM 347:2046, 2002

31. EHFG 5-8, Oct. 2005 31

32. EHFG 5-8, Oct. 2005 32 Potential Adulterants and Contaminants that Can Affect the Quality of Herbal Remedies NEJM 347:2046, 2002

33. EHFG 5-8, Oct. 2005 33 Potential Adverse Effects of Herbal Remedies and Their Major Constituents NEJM 347:2046, 2002

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

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