EHFG 5-8, Oct. 2005 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 EducationNational 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.

NEJM 352:12, 2005

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-CounterHerbal Medicines in 2003.

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

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)

Drug Metabolism Reviews 35:35, 2003

(from Zizyphi fructus)

CME = Crude methanolic extract; DAD = Diallyl disulfide; DAS = Diallyl sulfide; H = Human; M = Mouse; PH = PrimaryHepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort.

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 = PrimaryHepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort.

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 = PrimaryHepatocytes; PXR = Pregnane X receptor; R = Rat; SJW = St. John’s wort.

EHFG 5-8, Oct. 2005 11

Known Pharmacokinetic Herb-Drug Interactions (I)

Herb Interaction Drug Effect

Piperine Phenytoin, propranolol, theophylline, Curcumin (from Curcuma longa)

Increase the plasma AUC and Cmax (human)

Grape fruit juice Felodipine, terfenadine, saquinavir, cyclosporine, midazolam, triazolam, verapamil, lovastatin, cisapride, astemizole

Increase the oral bioavailability (human)

Danshen (from the root of Salvia miltiorrhiza)

R- and S- Warfarin Increase the AUC and Cmax

Decrease the clearance and apparent volume of distribution (rat)

Drug Metabolism Reviews 35:35, 2003

EHFG 5-8, Oct. 2005 12

Known Pharmacokinetic Herb-Drug Interactions (II)

Herb Interaction Drug Effect

Dong quai (from Angelica dahurica)

Tolbutamide Decrease the elimination

Diazepam Increase the Cmax fourfold

Khat (Catha edulis)

Ampicillin Reduce the bioavailability significantly

Ginseng Alcohol Decrease the blood concentration (human)

Enhance plasma clearance

Licorice Prednisolone Increase the AUC

Xiao Chai Hu Tang

Prednisolone Decrease the AUC

Tolbutamide Decrease the plasma concentration

Drug Metabolism Reviews 35:35, 2003

EHFG 5-8, Oct. 2005 13

Potential Interactions between Herbs and Conventional Drugs (I)

NEJM 347:2046, 2002

HerbConventional 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 glycosidesSince hawthorn may exert digitalis-like inotropic effects, it is prudent to monitor persons taking this herb in addition to digitalis glycosides closely.

EHFG 5-8, Oct. 2005 14

Potential Interactions between Herbs and Conventional Drugs (II)

NEJM 347:2046, 2002

HerbConventional 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).

EHFG 5-8, Oct. 2005 15

Potential Interactions between Herbs and Conventional Drugs (III)

NEJM 347:2046, 2002

HerbConventional 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.

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)

0 120

0

20

40

60

80

100

120

561P

% o

f In

hibi

tion

(Mea

n +

S.D

., n=

3)

The rank order of Chinese Herbal Enhancers

Positive control :Ketoconazole1 :HUCHE045;29 :HUCHE0112 :HUCHE023;30 :HUCHE0343 :HUCHE007;31 :HUCHE0394 :HUCHE035;32 :HUCHE0105 :HUCHE002;33 :HUCHE0226 :HUCHE032;34 :HUCHE0407 :HUCHE015;35 :HUCHE0338 :HUCHE050;36 :HUCHE0379 :HUCHE046;37 :HUCHE00410:HUCHE018;38 :HUCHE00811:HUCHE056;39 :HUCHE03612:HUCHE054;40 :HUCHE02613:HUCHE005;41 :HUCHE02814:HUCHE014;42 :HUCHE02015:HUCHE012;43 :HUCHE04816:HUCHE047;44 :HUCHE02417:HUCHE031;45 :HUCHE02518:HUCHE006;46 :HUCHE03019:HUCHE038;47 :HUCHE05620:HUCHE019;48 :HUCHE00321:HUCHE027;49 :HUCHE04422:HUCHE001;50 :HUCHE05523:HUCHE029;51 :HUCHE02124:HUCHE009;52 :HUCHE01725:HUCHE043;53 :HUCHE01326:HUCHE053;54 :HUCHE04227:HUCHE016;55 :HUCHE05128:HUCHE049;56 :HUCHE041

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

0 50 100 150 200 2500

2000

4000

6000

8000

10000

12000

control, n=9 with HUCHE015 20 mg/kg, n=9 positive control, n=5

sim

vast

atic

aci

d (n

g/m

L)

Mea

n +

S.E

.

Time (min)

0 50 100 150 200 250

100

1000

10000

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

Parameter (Unit) Control (B) with HUCHE015 (A) B/A Cmax (ng/mL) 203.1 33.2 (49.1) 11582.6 290.4 (7.5)＊＊ 57.0

Tmax (hr) 0.8 0.1 (50.3) 1.0 0.0 (0.0) 1.3 AUC0~t (hrng/mL) 312.1 64.5 (62.0) 15239.6 986.3 (19.4)＊＊ 48.8 AUCtotal (hrng/mL) 506.6 132.9 (78.7) 18675.4 1176.7 (18.9)＊＊ 38.1

k (1/hr) 0.47 0.11 (72.7) 0.64 0.03 (13.3) 1.4 T1/2 (hr) 2.1 0.4 (58.4) 1.9 0.1 (15.8) -

MRT (hr) 1.3 0.1 (23.1) 1.3 0.0 (5.0) 1.0

Data=mean S.E. (%CV)； *：p<0.05；**：p<0.01; n=9

EHFG 5-8, Oct. 2005 21

Fluvastatin HMG-CoA reductase inhibitor Specifically and extensively metabolized by CY

P2C9 Oral bioavailability: 20-30%

EHFG 5-8, Oct. 2005 22

Fluvastatin in SD Rats after Orally Administered Fluvastatin with or without Herbal Constituents

0 250 500 750 1000 1250 15000

60

120

180

control: without HUCHE070, n=7 sample: with HUCHE070, n=5

Flu

vast

atin

con

cent

ratio

n (n

g/m

L)M

ean

+ S

.E.

Time (min)

0 400 800 1200 1600

1

10

100

1000

*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 -agonist, -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

0

500

1000

1500

2000

2500

3000

0 5 10 15 20 25 30

Time (h)

Nal

buph

ine

(ng/

ml)

with HUCHE035

without HUCHE035

1

10

100

1000

10000

0 5 10 15 20 25 30

Time (h)

Nal

buph

ine

(ng/

ml)

*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

PK parameters Without HUCHE035 (A) With HUCHE035 (B) B/A

Cmax (ng/mL) * 79 18 2582 906 32.6

Tmax (min) 97 36 25 5 0.26

AUC0-t(min*ng/L) ** 21.4 8.8 218.2 67.6 10.2

AUCtotal (min*ng/L) * 24.4 8.9 244.1 69.5 10.0

(1/min) 0.0027 0.0007 0.0027 0.0006 1.0

t1/2 (min) 332 62 310 59 0.93

MRT (min) 496 90 316 103 0.64

CL/F (L/min/kg) ** 5.84 1.05 0.83 0.36 0.14

V/F (L/kg) * 2919 863 3774 170 1.3

Data = mean SE; * p < 0.05; ** p < 0.01

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, micro

organisms, 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 protoberb

erine alkaloids, green-tea leaf Neurotoxicity or convulsions: Kava rhizome Renal toxicity: -Aescin (saponin mixture from horse-chestnut

seed)

NEJM 347:2046, 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

NEJM 347:2046, 2002

EHFG 5-8, Oct. 2005 33

Potential Adverse Effects of Herbal Remedies and Their Major Constituents

NEJM 347:2046, 2002

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

EHFG 5-8, Oct. 2005 35

Induction of Various CYP Isoforms by Herbal Constituents (I)

Drug Metabolism Reviews 35:35, 2003