DK2404_half-series-title.qxd 4/17/06 2:51 PM Page i Herbal Supplements– Drug Interactions Scientific and Regulatory Perspectives edited by Y. W. Francis Lam University of Texas Health Science Center San Antonio, Texas, U.S.A. Shiew-Mei Huang FDA Center for Drug Evaluation and Research Silver Spring, Maryland, U.S.A. Stephen D. Hall Indiana University School of Medicine Wishard Memorial Hospital Indianapolis, Indiana, U.S.A. New York London Taylor & Francis is an imprint of the Taylor & Francis Group, an informa business Copyright © 2006 Taylor & Francis Group, LLC DK2404_Discl.fm Page 1 Thursday, March 2, 2006 9:51 AM Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 © 2006 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10987654321 International Standard Book Number-10: 0-8247-2538-7 (Hardcover) International Standard Book Number-13: 978-0-8247-2538-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. 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Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group is the Academic Division of Informa plc. Copyright © 2006 Taylor & Francis Group, LLC Preface Preface Although the potential of an interaction between concurrently administered botanical and pharmaceutical products is not unexpected, this topic has received increased attention and scrutiny over the past several years. The widespread use of botanical products in Western societies and the potency of modern pharmaceuticals have led to numerous reports of interaction, sometimes with significant adverse effects. While no one would argue for the need of another book related to drug interaction, this book differs from available books in several aspects. This book is not a standard book listing numerous reported botanical product-drug interactions organized by examples. Rather, the focus is to provide a timely discussion and perspective on the complex scientific and regulatory issues associated with investigating, reporting, and assessing these interactions in humans. From the beginning, our goal has been to provide information that is not readily available in other books covering the same topic. In addition to regulatory and industry perspectives, we have included a chapter describing interactions involving the more commonly used traditional Chinese medi- cine, and discussion regarding specific issues unique to this group of medic- inal products that needs to be taken into consideration when assessing the potential and significance of interaction. In contrast to single active compo- nents in modern pharmaceuticals, the presence of multiple active ingredients commonly present in botanical products underscores the importance of quality assurance and standardization in this emerging industry. The rele- vance and challenges of standardization for documentation and evaluation of botanical product-drug interactions are presented in depth in one chapter and, where applicable, discussed throughout the book. We realize that the terms herbs, herbal products, botanical products, and dietary supplements are often used interchangeably in the literature iii Copyright © 2006 Taylor & Francis Group, LLC iv Preface or sometimes even within the same context by consumer. While dietary sup- plements may be more easily recognized by consumers, the term includes vitamins, minerals, and other nutritional products that are not the focus of this book. On the other hand, it is generally accepted that herbs and bota- nical products also encompass different concentrated forms including extracts, powders, and formulated products containing a combination of different herbs. We used the term botanical products where applicable throughout the book because it denotes a more extensive scope than the more commonly used term herbs or herbal products, and it enables the inclu- sion of interaction involving citrus products as well. The book chapters are organized into five major sections. Section 1 (Chapters1to3)providesbackgroundinformationregardingbotanical usage and discusses several of the mechanisms in which botanical products can interfere with drug disposition and effect. The complex nature of bota- nical product-drug interaction and the different variables associated with interpretation of the reported interaction are highlighted in this section as well.Thesecondsection(Chapters4to7)focusesonbotanicalproducts that have been documented to interact with pharmaceutical products and, where applicable, their purported mechanism of interaction. Where possible, the contributors use specific examples in this section to illustrate the com- plexity of the issues in assessing the potential and significance of the inter- action.Thenextsection(Chapters8and9)providesanoverviewofthe pharmacokinetics of different botanical products, and discusses the impor- tance of quality assurance and standardization. The fourth section on regulatoryviewpoints(Chapters10to13)outlinestheFoodandDrug Administration’s approach to utilize the MedWatch program for documen- ting and evaluating reported botanical product-drug interactions. The last section(Chapters14and15)providesindustryandregulatoryperspectives on developing botanical products as pharmaceutical agents. This book is intended not only for scientists involved in the study of botanical product-drug interactions, but also for practitioners who advise patients on the safety concerns involved with using these products concur- rently. It is our sincere hope that the use of this book will serve to improve understanding of the complex issues associated with evaluating botanical product-drug interactions, which is an essential component in further develop- ing botanical products and obtaining regulatory approval as pharmaceu- tical agents. Y. W. Francis Lam Shiew-Mei Huang Stephen D. Hall Copyright © 2006 Taylor & Francis Group, LLC Contents Preface....iii Contributors....xi 1.TheLandscapeofBotanicalMedicineUtilization andSafety...................................1 Andrew Morris and Michael D. Murray Introduction....1 UtilizationofBotanicalDietarySupplements intheUnitedStates....2 SafetyofBotanicalProducts....8 Conclusions....19 References....19 2.DrugInteractionswithBotanicalProducts............25 Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall OverviewofBotanical–DrugInteractions....25 MechanismsofBotanical–DrugInteractions....26 AlteredPharmacokinetics....27 AlteredPharmacodynamics....34 AntagonisticPharmacodynamicEffect....37 EvaluatingBotanical–DrugInteraction....38 ConfoundingIssuesRelatedtoStudyDesign....41 Future....42 References....43 v Copyright © 2006 Taylor & Francis Group, LLC vi Contents 3.InVitroInhibitionwithBotanicalProducts...........49 Brian C. Foster, John T. Arnason, and Colin J. Briggs Background....49 NaturalProductVariation....50 TestConditions....62 ProductSelectionforClinicalStudies....63 Conclusion....64 References....65 4.DrugInteractionswithSt.John’sWort andEchinacea................................69 J. Christopher Gorski Introduction....69 St.John’sWort....70 Echinacea....92 References....95 5.BotanicalProducts–DrugInteractions:FocusonGarlic, GinkgoandGinseng..........................107 Y. W. Francis Lam and E. Ernst Introduction....107 Garlic(AlliumSativumL.)....108 Ginkgo(GinkgoBilobaL.)....112 AsianGinseng(PanaxGinsengC.A.Meyer)....115 Comment....118 References....119 6.AReviewofChineseBotanicalProduct–Drug Interactions................................123 Y. W. Francis Lam and Ming Ou Introduction....123 ChineseBotanicalProductsandWarfarin....125 ChineseBotanicalProductsandPhenprocoumon....133 ChineseBotanicalProductsandAspirin....134 ChineseBotanicalProductsandDigoxin....136 ChineseBotanicalProductsandDigoxin-like Immunoreactivity....137 LimitationsofCurrentLiterature....137 SpecificIssuesRegardingEvaluationofChineseBotanical Product–DrugInteractions....138 Copyright © 2006 Taylor & Francis Group, LLC Contents vii Conclusion....143 References....143 7.DrugInteractionsofGrapefruitandOther Citrus—WhatHaveWeLearned?.................147 S. U. Mertens-Talcott, I. Zadezensky, W. V. De Castro, VeronikaButterweck,andHartmutDerendorf