Clinically based evidence of drug–herb interactions: a systematic review

Importance of the field: Healthcare practitioners are deeply concerned about drug–herb interactions and how concurrent administration may affect both the safety and effectiveness of prescribed drugs. Interactions between botanical medicines and synthetic drugs can be clinically relevant and it is important to understand what kinds of interactions are possible. Better knowledge in this area will help avoid negative interactions and may also help enable synergistic interactions. Areas covered in this review: Includes articles related to the investigation of Western botanicals or whole herbal extracts in human subjects, investigating either the impact on Cytochrome P450 isoenzymes or an assessment of specific drug–herb interactions within a clinical trial. Searches were conducted in both Pubmed and EMBASE from inception to March 2009. What the reader will gain: Knowledge regarding specific interactions to consider in clinical practice. The reader will also gain an appreciation of the complexities associated with the area of drug–herb interactions. Summary tables of relevant drug–herb interactions are presented both for the individual herbs included and at the level of the CYP450 enzymes. Take home message: Knowledge of drug–herb interactions is limited and much more research needs to be done to further document clinically relevant interactions. Even though preclinical data are often poorly generalizable to the human situation, caution must be taken in the absence of clinical evidence especially where drugs with narrow therapeutic windows are concerned.

[1]  H. Leber,et al.  Influence of silymarin on drug metabolizing enzymes in rat and man. , 1976, Arzneimittel-Forschung.

[2]  S Yano,et al.  Effect of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. , 1990, Endocrinologia japonica.

[3]  F. Shimada,et al.  Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. , 1991, Endocrinologia japonica.

[4]  D. Nagel,et al.  The effect of garlic extract on human metabolism of acetaminophen. , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[5]  F. Gonzalez,et al.  Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. , 1994, Drug metabolism reviews.

[6]  D. Bailey,et al.  Grapefruit juice-drug interactions. , 1998, British journal of clinical pharmacology.

[7]  P. Kam,et al.  The physiological and pharmacological roles of cytochrome P450 isoenzymes , 1999, Anaesthesia.

[8]  E. Tanaka,et al.  Clinically significant pharmacokinetic drug interactions with psychoactive drugs: antidepressants and antipsychotics and the cytochrome P450 system , 1999, Journal of clinical pharmacy and therapeutics.

[9]  A. Riva.  Principles and Practice of Phytotherapy: Modern Herbal Medicine , 2000 .

[10]  G. Gerber.  Saw palmetto for the treatment of men with lower urinary tract symptoms. , 2000, The Journal of urology.

[11]  K. M. Lin,et al.  An open trial of nifedipine-herb interactions Nifedipine with St Johns wort, Ginseng or Ginkgo biloba , 2001 .

[12]  J. Falloon,et al.  Effect of Milk Thistle on the Pharmacokinetics of Indinavir in Healthy Volunteers , 2002, Pharmacotherapy.

[13]  G. Dresser,et al.  Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo , 2002, Clinical pharmacology and therapeutics.

[14]  N. Shear,et al.  Drug interactions: Proteins, pumps, and P-450s. , 2002, Journal of the American Academy of Dermatology.

[15]  J. Falloon,et al.  The effect of garlic supplements on the pharmacokinetics of saquinavir. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  Ying Ruan,et al.  Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers , 2003, Clinical pharmacology and therapeutics.

[17]  W. Peng,et al.  Effect of daidzein on CYP1A2 activity and pharmacokinetics of theophylline in healthy volunteers , 2003, European Journal of Clinical Pharmacology.

[18]  S. Khuder,et al.  Impact of Ginkgo Biloba on the Pharmacokinetics of Digoxin , 2003, American journal of therapeutics.

[19]  Kelly H. Jordan,et al.  Coadministration of Milk Thistle and Indinavir in Healthy Subjects , 2003, Pharmacotherapy.

[20]  J. Donovan,et al.  Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers , 2003, Clinical pharmacology and therapeutics.

[21]  D. Edwards,et al.  Influence of Goldenseal Root on the Pharmacokinetics of Indinavir , 2003, Journal of clinical pharmacology.

[22]  J. Donovan,et al.  Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[23]  Munir Pirmohamed,et al.  Cytochrome P450 enzyme polymorphisms and adverse drug reactions. , 2003, Toxicology.

[24]  T. Annesley,et al.  Interaction Study between Digoxin and a Preparation of Hawthorn (Crataegus oxyacantha) , 2003, Journal of clinical pharmacology.

[25]  K. Gallicano,et al.  Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. , 2003, British journal of clinical pharmacology.

[26]  J. Donovan,et al.  Multiple-Dose Administration of Ginkgo biloba Did Not Affect Cytochrome P-450 2D6 or 3A4 Activity in Normal Volunteers , 2003, Journal of clinical psychopharmacology.

[27]  D. Wei,et al.  Reversal of cancer multidrug resistance by green tea polyphenols , 2004, The Journal of pharmacy and pharmacology.

[28]  J. Donovan,et al.  GREEN TEA (CAMELLIA SINENSIS) EXTRACT DOES NOT ALTER CYTOCHROME P450 3A4 OR 2D6 ACTIVITY IN HEALTHY VOLUNTEERS , 2004, Drug Metabolism and Disposition.

[29]  Shiew-Mei Huang,et al.  The Effect of Echinacea (Echinacea purpurea Root) on Cytochrome P450 Activity in Vivo , 2004, Clinical pharmacology and therapeutics.

[30]  Tsuyoshi Ohkuni,et al.  Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. , 2004, Biological & pharmaceutical bulletin.

[31]  M. Waye,et al.  Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. , 2004, Pharmacogenetics.

[32]  R. Day,et al.  Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. , 2004, British journal of clinical pharmacology.

[33]  K. Wilson,et al.  Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis , 2005, European Journal of Clinical Pharmacology.

[34]  I. Khan,et al.  In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto , 2004, Clinical pharmacology and therapeutics.

[35]  K. Rajnarayana,et al.  Study on the Influence of Silymarin Pretreatment on Metabolism and Disposition of Metronidazole , 2004, Arzneimittelforschung.

[36]  J. Donovan,et al.  MULTIPLE NIGHT-TIME DOSES OF VALERIAN (Valeriana officinalis) HAD MINIMAL EFFECTS ON CYP3A4 ACTIVITY AND NO EFFECT ON CYP2D6 ACTIVITY IN HEALTHY VOLUNTEERS , 2004, Drug Metabolism and Disposition.

[37]  T. Karrison,et al.  Brief Communication: American Ginseng Reduces Warfarin's Effect in Healthy Patients , 2004, Annals of Internal Medicine.

[38]  Qiang Zhang,et al.  In vivo reversal of doxorubicin resistance by (-)-epigallocatechin gallate in a solid human carcinoma xenograft. , 2004, Cancer letters.

[39]  M. Nöldner,et al.  Influence of the Ginkgo extract EGb 761 on rat liver cytochrome P450 and steroid metabolism and excretion in rats and man , 2005, The Journal of pharmacy and pharmacology.

[40]  J. Nortier,et al.  Effect of Milk Thistle (Silybum marianum) on the Pharmacokinetics of Irinotecan , 2005, Clinical Cancer Research.

[41]  R. Day,et al.  Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. , 2005, British journal of clinical pharmacology.

[42]  I. Khan,et al.  In Vivo Effects of Goldenseal, Kava Kava, Black Cohosh, and Valerian on Human Cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 Phenotypes , 2005, Clinical pharmacology and therapeutics.

[43]  A. Izzo,et al.  Herb–drug interactions: an overview of the clinical evidence , 2005, Fundamental & clinical pharmacology.

[44]  S. Gardner,et al.  Clinical Assessment of Effects of Botanical Supplementation on Cytochrome P450 Phenotypes in the Elderly , 2005, Drugs & aging.

[45]  Bill Gurley,et al.  Assessing the Clinical Significance of Botanical Supplementation on Human Cytochrome P450 3A Activity: Comparison of a Milk Thistle and Black Cohosh Product to Rifampin and Clarithromycin , 2006, Journal of clinical pharmacology.

[46]  N. Seeram,et al.  Cranberry does not affect prothrombin time in male subjects on warfarin. , 2006, Journal of the American Dietetic Association.

[47]  M. Javors,et al.  The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects--a double blind placebo-controlled, crossover study. , 2006, Clinical nutrition.

[48]  M. Ducharme,et al.  Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans , 2006, Clinical pharmacology and therapeutics.

[49]  H. R. Wolf.  Does Ginkgo biloba Special Extract EGb 761® Provide Additional Effects on Coagulation and Bleeding when Added to Acetylsalicylic Acid 500mg Daily? , 2006, Drugs in R&D.

[50]  S. Yamada,et al.  Effects of Ginkgo Biloba Extract on Pharmacokinetics and Pharmacodynamics of Tolbutamide and Midazolam in Healthy Volunteers , 2006, Journal of clinical pharmacology.

[51]  S. Prabhakar,et al.  Effect of piperine on the steady‐state pharmacokinetics of phenytoin in patients with epilepsy , 2006, Phytotherapy research : PTR.

[52]  John W. Miller,et al.  Ginkgo biloba: Evaluation of CYP2C9 Drug Interactions In Vitro and In Vivo , 2006, American journal of therapeutics.

[53]  D. Greenblatt,et al.  Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: In vitro and clinical studies , 2006, Clinical pharmacology and therapeutics.

[54]  Chiu-Hsieh Hsu,et al.  Effects of Repeated Green Tea Catechin Administration on Human Cytochrome P450 Activity , 2006, Cancer Epidemiology Biomarkers & Prevention.

[55]  D. K. Williams,et al.  EFFECT OF MILK THISTLE (SILYBUM MARIANUM) AND BLACK COHOSH (CIMICIFUGA RACEMOSA) SUPPLEMENTATION ON DIGOXIN PHARMACOKINETICS IN HUMANS , 2006, Drug Metabolism and Disposition.

[56]  P. Neuvonen,et al.  Effects of Daily Ingestion of Cranberry Juice on the Pharmacokinetics of Warfarin, Tizanidine, and Midazolam—Probes of CYP2C9, CYP1A2, and CYP3A4 , 2007, Clinical pharmacology and therapeutics.

[57]  D. Greenblatt,et al.  A randomized, double-blind trial of the interaction between cranberry juice and warfarin , 2008, Journal of Thrombosis and Thrombolysis.

[58]  H. Xin,et al.  Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. , 2007, British journal of clinical pharmacology.

[59]  D. Murry,et al.  Pharmacogenetics of the Cytochrome P450 Enzyme System: Review of Current Knowledge and Clinical Significance , 2007 .

[60]  J. Zehnder,et al.  Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial , 2007, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[61]  D. K. Williams,et al.  Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans , 2007, Drug Metabolism and Disposition.

[62]  Soojin Park,et al.  Effect of Silymarin Supplement on the Pharmacokinetics of Rosuvastatin , 2008, Pharmaceutical Research.

[63]  J. Verweij,et al.  Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. , 2007, The oncologist.

[64]  H. Boon,et al.  Trends in complementary/alternative medicine use by breast cancer survivors: Comparing survey data from 1998 and 2005 , 2007, BMC women's health.

[65]  U. Fuhr,et al.  The effect of silymarin on oral nifedipine pharmacokinetics. , 2007, Planta medica.

[66]  B. Kalra,et al.  Cytochrome P450 enzyme isoforms and their therapeutic implications: an update. , 2007, Indian journal of medical sciences.

[67]  H. Juan,et al.  Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers , 2007, European Journal of Clinical Pharmacology.

[68]  M. Naidu,et al.  Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. , 2007, British journal of clinical pharmacology.

[69]  Y. Rao,et al.  EFFECT OF SILYMARIN ON THE ORAL BIOAVAILABILITY OF RANITIDINE IN HEALTHY HUMAN VOLUNTEERS , 2007, Drug metabolism and drug interactions.

[70]  D. K. Williams,et al.  Supplementation With Goldenseal (Hydrastis canadensis), but not Kava Kava (Piper methysticum), Inhibits Human CYP3A Activity In Vivo , 2008, Clinical pharmacology and therapeutics.

[71]  C. Flexner,et al.  Possible Differential Induction of Phase 2 Enzyme and Antioxidant Pathways by American Ginseng, Panax quinquefolius , 2008, Journal of clinical pharmacology.

[72]  D. K. Williams,et al.  Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. , 2008, Molecular nutrition & food research.

[73]  P. Barnes,et al.  Complementary and alternative medicine use among adults and children: United States, 2007. , 2008, National health statistics reports.

[74]  R. Davey,et al.  Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. , 2008, Current medical research and opinion.

[75]  R. Day,et al.  Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects , 2008, British journal of pharmacology.

[76]  D. Carrier,et al.  Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. , 2008, Molecular nutrition & food research.

[77]  R. McLendon,et al.  Splenda Alters Gut Microflora and Increases Intestinal P-Glycoprotein and Cytochrome P-450 in Male Rats , 2008, Journal of toxicology and environmental health. Part A.

[78]  Shu-Feng Zhou,et al.  An update on clinical drug interactions with the herbal antidepressant St. John's wort. , 2008, Current drug metabolism.

[79]  C. Flexner,et al.  Pharmacokinetic and metabolic effects of American ginseng (Panax quinquefolius) in healthy volunteers receiving the HIV protease inhibitor indinavir , 2008, BMC complementary and alternative medicine.

[80]  Q. Li,et al.  Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers , 2009, Xenobiotica; the fate of foreign compounds in biological systems.