Flavonoid Pharmacokinetic_ Phương pháp phân tích, dược động học tiền lâm sàng và lâm sàng, an toàn và độc tính (2013) Flavonoid Pharmacokinetics_ Methods of Analysis, Preclinical and Clinical Pharmacokinetics, Safety, and Toxicology (2013)
FLAVONOID PHARMACOKINETICS FLAVONOID PHARMACOKINETICS Methods of Analysis, Preclinical and Clinical Pharmacokinetics, Safety, and Toxicology Edited by NEAL M DAVIES Faculty of Pharmacy University of Manitoba Winnipeg, Manitoba, Canada JAIME A YÁÑEZ Drug Metabolism and Pharmacokinetics Alcon Research, Ltd., a Novartis Company Fort Worth, TX, USA A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2013 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 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any other commercial damages, including but not limited to special, incidental, consequential, or other damages For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data is available Printed in the United States of America ISBN: 9780470578711 10 9 8 7 6 5 4 3 2 Dedicated to my wife Claudia Davies and daughters Cassandra, Daniela, and Catalina, who have encouraged and supported me throughout the journey —Neal M Davies Dedicated to my mother Lillian Emperatriz Farfán Azpilcueta and my grandmother Hilda Regina Farfán Aspilcueta, whose inspirations live on with this book, and to all my family for their unconditional love, encouragement, and understanding —Jaime A Yáñez CONTENTS Foreword Preface Contributors 1 Polyphenols and Flavonoids: An Overview ix xiii xv Jaime A Yáñez, Connie M Remsberg, Jody K Takemoto, Karina R Vega-Villa, Preston K Andrews, Casey L Sayre, Stephanie E Martinez, and Neal M Davies 2 Analysis of Flavonoids through Chromatography 71 Jody K Takemoto, Stephanie E Martinez, and Neal M Davies 3 Chiral Methods of Flavonoid Analysis 117 Jaime A Yáñez, Casey L Sayre, Stephanie E Martinez, and Neal M Davies 4 Preclinical Pharmacokinetics of Flavonoids 161 Jaime A Yáñez, Casey L Sayre, and Neal M Davies 5 Clinical Pharmacokinetics of Flavonoids 195 Casey L Sayre, Karen D Gerde, Jaime A Yáñez, and Neal M Davies 6 Toxicology and Safety of Flavonoids 249 Stephanie E Martinez, Neal M Davies, and Jonathan K Reynolds 7 Flavonoids and Drug Interactions 281 Jaime A Yáñez, Nagendra V Chemuturi, Scott W Womble, Casey L Sayre, and Neal M Davies Index 321 vii FOREWORD Natural products have been used for hundreds and even thousands of years as food products and for therapeutic benefit Even today a large part of the world’s population relies on plants for their well-being What at first may seem surprising is that natural products continue to be popular in developed countries, including the US, Canada, Australia, the UK, and Europe However, this becomes understandable when one considers the factors that have led to the interest in and the continuing development of natural products in the marketplace Among these are concerns associated with development of pharmaceuticals, particularly the increasing cost of maintaining a pipeline and bringing the small number of successful molecules to market Developed societies continue to look toward natural products for many reasons, including a desire to maintain more control of their health care into older age, particularly given the greater awareness of side effects that have become apparent with some recently introduced drugs Despite the explosion of biotechnology, the pharmaceutical industry continues to utilize natural products for small molecule drug discovery, and over half of small drug molecules available today continue to have their origins in natural products The science behind natural products thus continues to be important and, indeed, essential if such agents are to continue to be used safely and effectively and as sources of new discoveries and therapies Polyphenols are being recognized more and more as important components of plant natural products There are some striking examples of the importance of such agents in health care, including components of green tea, red wine, and chocolate for cardiovascular disease protection and as adjunctive cancer management There are thousands of such compounds present in plants, and to ix x Foreword date we have only just begun to identify a relatively small percentage of such molecules from a small percentage of plants that have been screened from nature’s bounty Among the polyphenols are the group of molecules known as flavonoids While thousands of flavonoids have been identified many more remain unknown and undiscovered The potential for understanding the scientific basis of traditional medicine and for developing new therapies based on flavonoids remains enormous Advances in natural products must be based on the use of a multitude of techniques and practices Greater application of research methodologies is key to such development Only through understanding the structure and function relationships of molecules such as the flavonoids can we hope to apply what is commonly described as “reverse pharmacology”—that is, the discovery and improvement of therapies starting from traditional knowledge built over many generations in many cultures and then designing chemical, pharmacological, and clinical studies to validate and extend the value and understanding of such therapies in the context of today’s requirements for evidence-based therapeutic approaches This book covers the fundamental techniques that can be applied to natural product research and describes the science and methodology behind these techniques It then provides extensive examples of the outcomes from applications of these techniques Before the new chemical entities can be described, a variety of experimental methods of isolation, separation, and identification are needed—a complex process in natural medicines where one expects multicomponent and multi-target actions underpinning clinical effectiveness Furthermore, such understanding of the chemistry of flavonoids is essential if new molecules can be developed to overcome normal limitations of natural products and, hence, to provide wider application in modern therapy Principles that are common in pharmaceutical research, such as identifying metabolism and describing the role of chirality of natural products, are demonstrated in this scientific evaluation; and flavonoids provide excellent examples of this Only certain molecules have a primary role in many herbal medicines, while other components support the clinical effectiveness of the herb (such as moderating absorption and reducing toxic effects) The molecules responsible for all these attributes are often unknown As an example, willow bark is used for arthritis and pain; yet, while it is known that salicyn is a major component and a source of salicylic acid, it has become evident that the levels of salicylate produced in the body are insufficient to explain the clinical results Hence, one must search for other perhaps minor, but potent, components which account for the efficacy of willow bark These may well be flavonoids and other components known to be also present in the preparations, given the wide range of pharmacological actions that have been described for such compounds A major limitation of herbal natural product medicines for current therapeutic applications is the bioavailability of their various components Thus the effects obtained with natural medicines are generally slow to develop, often require high concentrations, and generally produce milder effects compared FOREWORD xi to, say, analgesics like paracetamol or aspirin (as is the case in the willow bark example above) Understanding metabolism and pharmacokinetics of the natural product components is key to understanding and ultimately improving the effectiveness of natural products, while still maintaining the benefits of their lower toxicity This is an emerging and less-researched area of natural medicines, and the authors of this book are world experts in this specialized pharmaceutical area They provide an excellent rationale for the experimental methods required in undertaking pharmacokinetic experiments, including the ADME parameters of absorption, distribution, metabolism, and excretion They follow this up with a comprehensive list of examples of pharmacokinetic studies that have been undertaken preclinically and clinically in the flavonoid area This is a major and important contribution of this book Such studies also lead to the appropriate use of natural products, particularly with respect to the potential for interactions, both positive and negative, between herbal natural medicines and pharmaceutical drugs and other foods and supplements In my own research, we have undertaken development of an herb–drug interaction database on such interactions; and this book provides an excellent source for studies of such interactions Overall, natural product state-of-the-art research is continuing to grow; and the need for more sophisticated research is growing Flavonoids is an important class of molecules in natural medicines and various other complementary medicine products which, while appreciated for a long time, rely on state-ofthe-art methodology for their understanding and for new discoveries Having a source of information on underpinning scientific methodology and extensively documented natural product research outcomes, as provided by this book, will be invaluable for all those interested in this area or wanting to gain a greater appreciation of the potential of this approach Basil D Roufogalis, PhD, DSc Professor Emeritus University of Sydney PREFACE There has been an increase in pharmaceutical and biomedical therapeutic interest in natural products as reflected in the sales of nutraceuticals and functional foods and in the global therapeutic use of traditional medicines over the last decade The use of traditional medicines is based on knowledge, skills, and practices founded on experiences and theories from different cultures Traditional medicines are used to prevent and maintain health, which may ultimately improve and/or treat physical and mental illnesses The present day use of these products encompasses almost every aspect of our daily lives from health and beauty, dietary supplements, performance enhancement supplements, and food and beverage to overall health and well-being products Over the last 30 years, scientific investigations have illustrated the therapeutic bioactivity of flavonoids in chronic disease studies and have piqued the interests of scientists from the diverse fields of nutrition, food, horticulture, and pharmaceutical sciences Additionally, increased interest by nutraceutical manufacturers has created an abundance of flavonoid-containing dietary supplements on the market These products and others like them are consumed by a large percentage of the Western population Since dietary supplements are viewed by most regulatory agencies as food rather than drugs, many of these products are produced without having passed standards of safety or efficacy The use of flavonoid-containing nutraceuticals presents a potential public health risk that could be ameliorated by flavonoid-specific research generated from a variety of fields Hence, the objective of this book is to provide the framework for fundamental concepts and contemporary practice of methods of analysis for achiral and chiral flavonoids, preclinical and clinical pharmacokinetics, as well as toxicology and safety of flavonoids and their possible drug interactions xiii xiv Preface It is our belief that this book provides the basic concepts to a novice graduate student and the advanced knowledge to a veteran pharmaceutical, food, or nutrition scientist Chapter provides a comprehensive overview of polyphenols and flavonoids The methods of analysis of achiral flavonoids using chromatography are covered in Chapter 2, while methods of analysis for chiral flavonoids are described in Chapter Chapters and present the advanced concepts of preclinical and clinical pharmacokinetics of flavonoids, respectively The toxicology and safety of flavonoids is presented in Chapter 6, while the reported flavonoid–drug interactions are detailed in Chapter The various topics of this book can be adapted by scientists to their specific research needs This book contains diverse topics that required a multidisciplinary effort, which would not have been possible without the great efforts of our contributors We really appreciate the expertise, willingness, and patience of our contributors during the completion process of this book project We would like to express our sincere thanks to Mr Jonathan Rose for his support, patience, and confidence in us We would also like to express our appreciation to our families and colleagues for their support and encouragement Finally, we would like to thank Professor Basil Roufogalis, an innovator and world leader in herbal medicine research and education, for writing such an inspiring foreword for this book Neal M Davies, PhD Jaime A Yáñez, PhD 324 Chiral flavonoids (cont’d) structures of, 122t–125t synthesis of, 7, 7f Chirality, defined, 118 Chiral methods of flavonoid analysis, 117–150 for catechins, 148–149 catechin, 148–149 catechin gallate, 149 epicatechin, 149 epicatechin gallate, 150 epigallocatechin, 150 epigallocatechin gallate, 150 gallocatechin, 150 enantiomer separation with chromatography, 126–133 for flavanones, 136–148 eriocitrin and eriodictyol, 137–139 flavanone, 138–139 hesperidin and hesperetin, 139–141 homoeriodictyol, 141 isosakuranetin, 141–142 isoxanthohumol, 148 liquiritigenin, 142, 142f naringin and naringenin, 143–145 narirutin, 145 neoeriocitrin, 145 neohesperidin, 145–146 pinocembrin, 146, 146f pinostrobin, 147, 147f 6-prenylnaringenin, 148 8-prenylnaringenin, 148 prunin, 147 sakuranetin, 147–148 taxifolin, 148 pros and cons of current methods, 136 Chiral mobile phase, additives to, 130–133 CHIRALPAK columns, 126–128, 137–140, 142–149 Chiral stationary phase (CSP) cyclodextrin columns, 129–130 polysaccharide columns, 126–128 Chlorogenic acid, 302f, 303 Chromatography, 71–109 applications of, 74–75 chiral columns, 101, 126–130, 136 derivatization, 85, 88–89 INDEX detection, 88–97 electrochemical detection, 96 fluorescence detection, 90–91 mass spectrometry, 91–94, 94f nuclear magnetic resonance (NMR), 95–96 photodiode array detection, 89–90 ultraviolet-visible detection, 89–90 enantiomer separation with, 126–133 additives to chiral mobile phase, 130–133 chiral derivatization techniques, 133 chiral stationary phase (CSP), 126–130 future directions for, 107–109 history of, 74 method development, 97–103 distribution ratio and, 97–98 extraction, 102–103 mobile phase, 98–100, 98f physiochemical properties, 97–98 processing, 102–103 standards, 101–102 stationary phase, 100–101 mobile phase considerations, 98–100 flow rate, 99 isocratic versus gradient elution, 99–100 solvent polarity spectrum, 98f temperature and pH, 100 techniques, 76f adsorption chromatography, 79–85 affinity chromatography, 75–76 capillary electrochromatography, 86 chip use, 108 gas chromatography, 80–81 gas-liquid chromatography, 79 gas-solid chromatography, 79 GC-GC (two-dimensional GC) chromatography, 81, 85 high pressure liquid chromatography, 81–82, 87–88 high pressure thin-layer chromatography, 107 hydrophilic interaction liquid chromatography, 83 ion-exchange chromatography, 76–78 liquid chromatography, 81, 85 INDEX liquid chromatography-gas chromatography, 86–87 liquid-liquid chromatography, 78–79 liquid-solid chromatography, 81–82, 87 multidimensional chromatography, 87 nano-LC and nano-ESI-MS/MS, 108 normal-phase liquid chromatography, 83 paired chromatography, 85–88 partition chromatography, 78–79 reversed-phase chromatography, 82 reversed-phase high performance liquid chromatography, 83, 88 reversed-phase liquid chromatography, 83 selection of, 75 two-dimensional thin-layer chromatography, 87 ultrahigh performance liquid chromatography, 85, 108 validation, 103–106 accuracy, 105 peak shape and distribution, 104–105 precision, 105 recovery, 106 selectivity, 105 sensitivity, 105 stability, 106 standard curves, 104 Chromones, synthesis of, 7, 7f Chromone synthase, Chrysin ABC transporters and, 291, 293t BCRP transporter and, 299, 300t clinical pharmacokinetic studies, 211t MRP2 transporter and, 299 P-glycoprotein interaction, 295 Cianidanol hemolytic anemia and, 257 renal toxicity, 256 structure of, 256f Cidofovir, 302 Cinnamate 4-hydrolase (C4H), 6–7 Cisplatin, 235t 325 Clinical pharmacokinetics of flavonoids, 195–241 chiral flavonoids, 237–238 Phase I studies, 217t–226t drug effects on flavonoid pharmacokinetics described, 240 studies, 234t–236t flavonoid derivatives, 238 Phase I studies, 226t–228t flavonoid effects on pharmacokinetics of other drugs described, 238–240 studies, 228t–234t methods of analysis, 196 nonchiral flavonoids, 196, 237 Phase I studies, 197t–217t studies, 197t–236t chiral flavonoids, 217t–226t drug effects on flavonoid pharmacokinetics, 234t–236t flavonoid derivatives, 226t–228t flavonoid effects on pharmacokinetics of other drugs, 228t–234t nonchiral flavonoids, 197t–217t Clozapine, 303 Cochicines, 295 Cocoa-milk, 227t Cocoa-water, 226t–227t Colitis, flavonoids and, 250–251 Contact dermatitis, flavonoids and, 266–267 Coumarins, synthesis of, 7–8, 7f Coumarin synthase, Coumestrol, ABC transporters and, 292 C-quercetin, clinical pharmacokinetic studies on, 203t C ring, Cunninghamella elegans, 32–33 Cyanidin, absorption of, 164 Cyanidin-3-arabinoside absorption of, 165 clinical pharmacokinetic studies, 216t Cyanidin-3-galactoside absorption of, 164–165 clinical pharmacokinetic studies, 216t 326 Cyanidin-3-glucoside absorption of, 163–165 clinical pharmacokinetic studies, 197t, 199t–201t, 216t Cyanidin-3-glycosylrutinoside absorption of, 163 Cyanidin-3-O-glucoside, clinical pharmacokinetic studies on, 197t Cyanidin-3-rutinoside absorption of, 163–164 clinical pharmacokinetic studies, 198t, 201t Cyanidin-3-sambubioside, clinical pharmacokinetic studies on, 198t–201t Cyanidin-3-sophoroside, absorption of, 163 Cyanidin-3-xylosylrutinoside, clinical pharmacokinetic studies on, 198t Cyclobond columns, 129, 133, 138–140, 143–147, 149 Cyclodextrin addition to chiral mobile phases, 130–132 columns, 129–130 Cyclooxygenase-1 and -2 inhibitory activity eriocitrin and eriodictyol, 29 hesperidin and hesperetin, 16–17 naringin and naringenin, 22–23 Cyclosporine, 232t, 239, 286–287 CYP1A1, 24 CYP1A2, 303 CYP2A6, 24 CYP3A4, 23–25, 288, 303 CYP3A5, 24 CYP2C8, 303 CYP2D6, 24 Cytochrome P450 flavonoid effect on, 11, 73 intestinal isoforms, 290 by naringin and naringenin, 23–25 interaction P-glycoprotein (P-gp, ABCB1), 296, 297t, 298 CZE (capillary zone electrophoresis), 86 INDEX Daidzein ABC transporters and, 292 absorption of, 166, 167f, 168 BCRP transporter and, 299 clinical pharmacokinetic studies, 206t–207t, 208t–210t distribution of, 178, 179f equol as metabolite of, 118 female reproductive toxicity, 263 hepatic toxicity, 255 male reproductive toxicity, 261 medicinal use, 196t metabolites of, 238 pharmacokinetics, 237 placental transfer, 178, 179f racemic dihydrodaidzein and, 121 structure of, 255f Darunavir, 288 Daunomycin, 295, 298 Dehydrofelodipine, 230t–231t Deiodinase, 264 Delphinidin absorption of, 164–165 structure of, 260f Delphinidin-3-glucoside absorption of, 164–165 clinical pharmacokinetic studies, 201t Delphinidin-3-rutinoside absorption of, 164–166 clinical pharmacokinetic studies, 201t Delphinidin-3-sambubioside, clinical pharmacokinetic studies on, 199t Derivatization, 85, 88–89 Dermatitis, flavonoids and, 267 Detection methods, 88–97 electrochemical detection, 96 fluorescence detection, 90–91 mass spectrometry, 91–94, 94f nuclear magnetic resonance (NMR), 95–96 photodiode array detection, 89–90 two-dimensional thin-layer chromatography, 87 ultraviolet-visible detection, 89–90 Diarrhea, flavonoids and, 250–251 Diastereoisomerization, 134 Diastereoisomers, 126, 130 Diclofenac, 230t, 239 INDEX Didymin, 36 Diet food intake and flavonoid-drug interactions, 287–289 polyphenols in, 9, 73 Diethylstilbestrol (DES) female reproductive toxicity, 262–263 male reproductive toxicity, 260–261 structure of, 261f Digoxin, 295–296, 297t, 298 Dihydrochalcones, 8f Dihydrogenistein, 184 Dihydrokaempferol, 39f Dihydroxyflavanols, structure of, 119, 120f 3,4-dihydroxyphenylacetaldehyde, 41f 3,4-dihydroxyphenylacetic acid, 41f, 42f Diltiazem, 296, 297t, 298 4′,7-dimethoxyisoflavone, 295 Diosmetin CYP450 inhibition, 303 Diosmin colitis and, 251 CYP 450 interaction, 196t medicinal use, 196t P-glycoprotein interaction, 295 pharmacokinetic studies, 230t structure of, 252f Distribution of flavonoids, 161, 175–180 Doxorubicin, 295 DPPH (diphenylpicrylhydrazyl radical), 20, 27–28, 31 Dracocephins, 121 Dracorupesins, 121 Drug discovery expense of, time required for, Drug interactions, 196t, 281–304 beverage intake and, 286–287, 287f–288f drug effects on flavonoid pharmacokinetics described, 240 studies, 234t–236t flavonoid effects on pharmacokinetics of other drugs described, 238–240 studies, 228t–234t 327 flavonoid subclasses and interaction with metabolic enzymes and transporters, 283t food intake and, 287–289 herb intake and, 282, 284, 284f–286f studies on, 289–290 transporter-mediated interactions, 283t, 290–303 ABC transporters, 290–301, 293t–294t breast cancer resistance protein (BCRP, ABCG2), 290–292, 293t–294t, 299–301, 300t experimental techniques to study, 292 multidrug resistance protein (MRP2, ABCC2), 290–291, 293t–294t, 298–299 organic anion transporters (OATs), 301–303, 302f P-glycoprotein (P-gp, ABCB1), 24–25, 31, 284–287, 290–292, 293t–294t, 295–296 CYP450 interaction, 296, 297t, 298 Ductus arteriosus, prenatal closure of, 267–268 Electromigration, 85–86 Electron multiplier detector, 94 Electrospray ionization (ESI), 91–93 Ellagic acid clinical pharmacokinetic studies, 197t OAT transporters and, 302 structure of, 260f topoisomerase inhibition, 259 Ellagitannins, excretion of, 185–186 Emodin, absorption of, 162 Enantiomerization, 10, 120, 133–136 See also Chiral flavonoids; Chiral methods of flavonoid analysis Enantiomers separation with chromatography, 126–133 additives to chiral mobile phase, 130–133 chiral derivatization techniques, 133 chiral stationary phase (CSP), 126–130 328 Enantiomers (cont’d) spatial distribution of chiral flavanones, 118f stereochemical stability, 119–120 Endocrine system, toxicology of flavonoids and, 260–265 female reproductive toxicity, 262–263 male reproductive toxicity, 260–262 thyroid, 264–265, 264t Enrofloxacin, 299 Ent- (prefix), 10 Epicatechin ABC transporters and, 291, 293t absorption of, 172 chiral resolution of, 149–150 clinical pharmacokinetic studies, 220t–223t, 226t enantiomers, 121 metabolism of, 180, 182 P-glycoprotein interaction, 295 structure of, 125t Epicatechin gallate absorption of, 172–173 chiral resolution of, 150 hepatic toxicity, 253 structure of, 125t, 253f Epicatechin-3-gallate absorption of, 172–173 hepatic toxicity, 253 structure of, 253f Epicatechin-O-sulfate, clinical pharmacokinetic studies on, 226t–227t Epigallocatechin chiral resolution of, 150 clinical pharmacokinetic studies, 218t–225t enantiomers, 121 hepatic toxicity, 253 pharmacokinetics, 237–238 structure of, 125t, 253f Epigallocatechin gallate absorption of, 172–173 chiral resolution of, 150 distribution of, 175–176 excretion of, 184 hepatic toxicity, 253–254 metabolism of, 180, 181f–182f structure of, 125t, 253f INDEX Epimerization, 120, 134–136 Equol, 118–119, 121, 282 clinical pharmacokinetic studies, 218t, 226t–228t female reproductive toxicity, 262 pharmacokinetics, 238 Eriocitrin chiral resolution of, 137 pharmacological activity, 26–29 antibacterial activity, 26–27 anticancer activity, 28–29 antiinflammatory activity, 27 antimutagenic activity, 29 antioxidant activity, 27–28 cyclooxygenase-1 and -2 inhibitory activity, 29 structure of, 26f, 122t Eriodictyol absorption of, 162 chiral resolution of, 137 enantiomers, 121 pharmacological activity, 26–29 antibacterial activity, 26–27 anticancer activity, 28–29 antiinflammatory activity, 27 antimutagenic activity, 29 antioxidant activity, 27–28 cyclooxygenase-1 and -2 inhibitory activity, 29 structure of, 27f, 122t ESI (electrospray ionization), 91–93 Estrogen(s) female reproductive toxicity, 263 flavonoid synthesis from, 8, 8f hepatic toxicology of flavonoids and, 255 Estrogenic effect of hesperidin and hesperetin, 17 Estrogen receptor (ER), 21, 178, 261, 263 Estrone sulfate, 287, 288f, 302, 302f Etoposide, 297t, 298 Excretion/elimination of flavonoids, 161, 184–186 Felodipine, 230t, 239 Female reproductive toxicity, 262–263 Fexofenadine, 231t–232t, 239, 286 INDEX Fisetin structure of, 260f topoisomerase inhibition, 259 Flavanoids See Flavonoids; specific compounds Flavan-3-ols interaction over metabolic enzymes and transporters, 283t sources of, 287–288 structure of, 6f Flavanols, sources of, 287–288 Flavanone(s) chiral resolution of, 136–148 eriocitrin and eriodictyol, 137–139 flavanone, 138–139 hesperidin and hesperetin, 139–141 homoeriodictyol, 141 isosakuranetin, 141–142 isoxanthohumol, 148 liquiritigenin, 142, 142f naringin and naringenin, 143–145 narirutin, 145 neoeriocitrin, 145 neohesperidin, 145–146 pinocembrin, 146, 146f pinostrobin, 147, 147f 6-prenylnaringenin, 148 8-prenylnaringenin, 148 prunin, 147 sakuranetin, 147–148 taxifolin, 148 interaction over metabolic enzymes and transporters, 283t racemic, 119 sources of, 5, 9, 287–288 stereochemically pure, 121 structure of, 6f, 119, 122t synthesis of, 7f Flavones interaction over metabolic enzymes and transporters, 283t sources of, 72, 287 structure of, 6f Flavonoids astringency in foods and, 72–73 chirality in, 9–10 (see also Chiral flavonoids) chiral methods of analysis, 117–150 329 clinical pharmacokinetics, 195–241 dietary intake levels, as glycoside, numbering pattern, 4f preclinical pharmacokinetics, 161–186 sources of, 8–10 structure of, 4f, 5f synthesis of, 4–8, 7f toxicology and safety, 249–268 Flavonols interaction over metabolic enzymes and transporters, 283t structure of, 6f Flavopiridol ABC transporters and, 292 clinical pharmacokinetic studies, 212t–217t, 234t–236t diarrhea and, 250–251 drug interactions, 240 pharmacokinetics, 237 structure of, 251f Flavoxate clinical pharmacokinetic studies, 212t glaucoma development and, 265 hepatic toxicology, 254–255 pharmacokinetics, 237 structure of, 254f Fluorescence detection, 90–91 Folin-Ciocalteu reagent, 11, 73–74 Folin-Denis reagent, 11, 73–74 Food intake, flavonoid-drug interactions and, 287–289 French paradox, 44 Gallic acid in bound form, 72 pharmacological activity, 43–45 structure of, 44f Gallocatechin chiral resolution of, 150 enantiomers, 121 structure of, 125t Gas chromatography (GC), 80–81 Gas-liquid chromatography (GLC), 79 Gas-solid chromatography (GSC), 79 Gastric emptying, St John’s wort effect on, 285, 285f 330 Gastrointestinal tract, toxicology of flavonoids and, 250–251 colitis, 250–251 diarrhea, 250–251 GC-GC (two-dimensional GC) chromatography, 81, 85 Genistein ABC transporters and, 291–292, 293t absorption of, 166, 167f, 168 BCRP transporter and, 299 clinical pharmacokinetic studies, 206t–211t distribution of, 176, 178–180 as estrogen agonist, 260 excretion of, 184–185, 185f female reproductive toxicity, 263 hepatic toxicity, 255 lactational transfer of, 179–180 leukemia induction and, 259 male reproductive toxicity, 261 metabolism of, 183–184 MRP2 transporter and, 298–299 P-glycoprotein interaction, 297t, 298 pharmacokinetics, 237 placental transfer of, 78 racemic dihydrogenistein and, 121 structure of, 255f topoisomerase inhibition, 259 Ginkgo, 285, 286f Ginkgolide A, clinical pharmacokinetic studies on, 211t–212t Ginkgolide B, clinical pharmacokinetic studies on, 211t–212t Glabridin ABC transporters and, 291 clinical pharmacokinetic studies, 217t Glaucoma development, toxicology of flavonoids and, 265 GLC (gas-liquid chromatography), 79 Glucose transport, phloretin inhibition of, 30–31 GLUT2 transporters, inhibition of, 30 Glycitein clinical pharmacokinetic studies, 210t structure of, 261f Goiter, 265 Grapefruit See Hesperidin; Naringin INDEX Green tea catechin, distribution of, 178–179 GSC (gas-solid chromatography), 79 Health benefits of polyphenols, 9, 11, 73 Hemolytic anemia, 257 Hepatic toxicology of flavonoids, 251–256 dietary estrogens, 255 flavoxate, 254–255 isoflavones and hepatocellular carcinoma, 255–256 tea consumption and, 252–254 Hepatocellular carcinoma, 255–256 Heptamethoxyflavone, 295 Herb intake, flavonoid-drug interactions and, 282, 284, 284f–286f Hesperetin absorption of, 162, 171 BCRP transporter and, 299–301 chiral resolution of, 139–141 CYP450 inhibition, 303 pharmacokinetics, 238 pharmacological activity, 12–17 antiadipogenic activity, 17 anticancer activity, 15–16 antifungal, antibacterial, antiviral activity, 12–13 antiinflammatory activity, 13–14 antioxidant activity, 14–15 cyclooxygenase-1 and -2 inhibitory activity, 16–17 estrogenic effect, 17 structure of, 12f, 122t Hesperidin chiral resolution of, 139–141 colitis and, 251 pharmacological activity, 12–17 antiadipogenic activity, 17 anticancer activity, 15–16 antifungal, antibacterial, antiviral activity, 12–13 antiinflammatory activity, 13–14 antioxidant activity, 14–15 cyclooxygenase-1 and -2 inhibitory activity, 16–17 estrogenic effect, 17 structure of, 12f, 122t, 252f 331 INDEX High pressure liquid chromatography (HPLC), 81–82, 87–88 chiral resolution and, 137–140, 143–149 High pressure thin-layer chromatography (HPTLC), 107 HILIC (hydrophilic interaction liquid chromatography), 83 Homoeriodictyol chiral resolution of, 141 enantiomers, 121 pharmacokinetic studies, 33–34 pharmacological activity, 32–34 structure of, 122t HPLC See High pressure liquid chromatography HPTLC (high pressure thin-layer chromatography), 107 Hydrokaempferol chalcone, in taxifolin metabolism, 41f Hydrophilic interaction liquid chromatography (HILIC), 83 Hydroxybenzoic acids examples of, 5, 72 structure, 5f Hydroxybupropion, 233t Hydroxycinnamic acids examples of, 5, 72 structure, 5f 3-hydroxyflavanones, 119, 120f Hydroxymaackiain, 121 Hydroxymidazolam, 234t Hypeforin, clinical pharmacokinetic studies on, 205t–206t Hypericin, clinical pharmacokinetic studies on, 204t–205t Hyperoside, absorption of, 174 Indinavir, 229t, 238 Infertility dietary estrogens and, 263 flavonoids and, 262 genistein and, 263 Ion-exchange chromatography (IEC), 76–78 Ion exchanger molecular weights, 78 selection of, 77 Irinotecan, 235t–236t, 240 Iron deficiency anemia, 257–259 Isoflavone reductase, 121 Isoflavones chiral, 121 hepatocellular carcinoma and, 255–256 interaction over metabolic enzymes and transporters, 283t sources of, 5, 72 structure of, 6f Isoliquiritigenin, structure of, 251f Isomerization, 10 Isoquercitrin, absorption of, 174 Isorhamnetin ABC transporters and, 291 clinical pharmacokinetic studies, 205t–206t Isosakuranetin biosynthesis of, 35 chiral resolution of, 141–142 pharmacokinetic studies, 36 pharmacological activity, 34–36 structure enantiomers, 34f glycosides, 35f structure of, 123t Isoscutellarin, clinical pharmacokinetic studies on, 206t Isosilybin A, clinical pharmacokinetic studies on, 201t–202t Isosilybin B, clinical pharmacokinetic studies on, 201t–202t Isoxanthohumol, chiral resolution of, 148 Kaempferol ABC transporters and, 291, 293t CYP450 inhibition, 303 leukemia induction and, 259 P-glycoprotein interaction, 295 structure of, 260f 2-keto-3-(3,4-dihydroxyphenyl)propionic acid, 41f Kidney See Renal toxicology of flavonoids Langmuir isotherm, 104–105 Leukemia induction, 259 Leuocyanidin oxygenase, 7, 7f 332 Lignans structure, 5f synthesis of, 7–8, 7f Lignan synthase, Like dissolves like, 79, 83, 98 Linear isotherm, 104 Liquid chromatography (LC) described, 81, 85 mass spectrometry paired with, 94 Liquid chromatography-gas chromatography (LC-GC), 86–87 Liquid-liquid chromatography (LLC), 78–79 Liquid-liquid extraction (LLE), 102–103 Liquid-solid chromatography (LSC), 81–82, 87 Liquiritigenin chiral resolution of, 142, 142f structure of, 123t, 142f Liver See Hepatic toxicology of flavonoids Losartan, 228t–229t, 238 Luteolin absorption of, 164 antithyroid activity, 265 colitis and, 251 excretion of, 185 structure of, 252f topoisomerase inhibition, 259 Maackiain, 121 Male reproductive toxicity, 260–262 Malvidin absorption of, 164–165 male reproductive toxicity, 262 structure of, 261f Malvidin-3-glucoside absorption of, 163–165 clinical pharmacokinetic studies, 199t–200t, 217t MAPK inhibitor, 21–22 Mass spectrometry, 91–94 atmospheric pressure chemical ionization (APCI), 92 detectors, 94 electrospray ionization (ESI), 91–93 ionization choices, 92–93 mass analyzer, 93–94 schematic, 91f INDEX selected ion mode (SIM), 92 tandem MS, 94 Mass-to-charge ratio (m/z), 92–93 Matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) MS, 94, 109 MDR (multi-drug resistant) efflux pump, 31 Medicarpin, 121 Medicinal uses of flavonoids, 196, 196t Metabolism of flavonoids, 161, 180–184 Metronidazole, 229t–230t, 238–239 Micellar electrokinetic chromatography (MEKC), 131–132, 137, 140–144, 146, 147–150 Microcrystalline cellulose triacetate (MCCTA), 126–127, 137, 140–141, 143–144, 146 Midazolam, 234t, 240 Migraines, 265–266 Mitoxantrone, 299, 301 Mixed lineage leukemia (MLL), 259 7-monohydroxyethylrutoside, absorption of, 173–174 Mono-3′-O-(B-hydroxyethyl)-quercetin, clinical pharmacokinetic studies on, 227t Mono-4′-O-(B-hydroxyethyl)-quercetin, clinical pharmacokinetic studies on, 227t Morin ABC transporters and, 294t hepatic toxicity, 254 P-glycoprotein interaction, 297t, 298 structure of, 254f Mortality, causes of, 73 Moxidectin, 297t, 298 Multidrug resistance protein (MRP2, ABCC2), 290–291, 293t–294t, 298–299 Multi-drug resistant (MDR) efflux pump, 31 Myricetin, 299 Nanochitosan, 128 Nano-LC and nano-ESI-MS/MS, 108 Naringenin ABC transporters and, 294t absorption of, 162, 171 BCRP transporter and, 299 333 INDEX biotransformation pathway, 39f chiral resolution of, 143–145 CYP450 inhibition, 303 enantiomers, 118–119 P-glycoprotein interaction, 297t pharmacokinetics, 238 pharmacological activity, 17–26 antiadipogenic activity, 23 anticancer activity, 20–22 antifungal, antibacterial, and antiviral activity, 18–19 antigenotoxic properties, 25 antiinflammatory activity, 19–20 antioxidant activity, 20 cardioprotective effects, 23 cyclooxygenase-1 and -2 inhibitory activity, 22–23 effect on cytochrome P450, 23–25 radioprotection, 25–26 structure of, 18f, 123t Naringenin chalcone, 39f Naringin absorption of, 171 chiral resolution of, 143–145 CYP450 inhibition, 303 P-glycoprotein interaction, 296, 297t pharmacological activity, 17–26 antiadipogenic activity, 23 anticancer activity, 20–22 antifungal, antibacterial, and antiviral activity, 18–19 antigenotoxic properties, 25 antiinflammatory activity, 19–20 antioxidant activity, 20 cardioprotective effects, 23 cyclooxygenase-1 and -2 inhibitory activity, 22–23 effect on cytochrome P450, 23–25 radioprotection, 25–26 sources of, 289 structure of, 18f, 123t Narirutin chiral resolution of, 145 sources of, 289 structure of, 123t Neoangiogenesis, 22 Neoeriocitrin chiral resolution of, 145 structure of, 123t Neoflavonoids, 7f, Neohesperidin chiral resolution of, 145–146 structure of, 124t Nifedipine, 289 Nisoldipine, 289 Nitrofurantoin, 299–300, 300t Nobiletin, 295 Nomenclature of flavonoids, 10 Nonacylated anthocyanins, clinical pharmacokinetic studies on, 199t Normal-phase liquid chromatography (NP-LC), 83 Norverapamil, 233t–234t Nothofagin, 30 Nuclear magnetic resonance (NMR), 95–96 Nutriceuticals, 1, 72, 117 NV06 See Phenoxodiol NV-52, clinical pharmacokinetic studies on, 202t Obesity See Antiadipogenic activity Ochratoxin A, 299 Ocular responses to flavonoids, 265 O-methyl (epi)catechin-o-sulfate, clinical pharmacokinetic studies on, 227t Organic anion transporters (OATs), 292, 301–303, 302f Organic anion-transporting polypeptide (OATP), 286–287, 288f Paclitaxel, 236t, 240, 296, 297t, 298 Paired chromatography, 85–88 PAL (phenylalanine ammonia-lyase), Partial least squares, 295 Partition chromatography, 78–79 PCD (permanent clover disease), 262 P-coumaric acid, 5, 72 Peak area ratio (PAR), 101 Peak shape, chromatography, 104–105 Pelargonidium, absorption of, 166 Peonidin, absorption of, 164 Peonidin-3-arabinoside, clinical pharmacokinetic studies on, 217t 334 Peonidin-3-galactoside, clinical pharmacokinetic studies on, 217t Peonidin-3-glucoside absorption of, 164 clinical pharmacokinetic studies, 199t, 200t, 217t Peppermint See Eriocitrin Permanent clover disease (PCD), 262 Peroxynitrite, 14 Petunidin, absorption of, 164 Petunidin-3-glucoside, clinical pharmacokinetic studies on, 200t P-glycoprotein (P-gp, ABCB1), 24–25, 31, 284–287, 290–292, 293t–294t, 295–296 CYP450 interaction, 296, 297t, 298 Pharmacokinetics See also Drug interactions; Pharmacokinetic studies; specific flavonoid compounds absorption, 161, 162–175 distribution, 161, 175–180 drug interactions and, 282 excretion/elimination, 161, 184–186 metabolism, 161, 180–184 preclinical, 161–186 Pharmacokinetic studies clinical, 197t–236t chiral flavonoids, 217t–226t drug effects on flavonoid pharmacokinetics, 234t–236t flavonoid derivatives, 226t–228t flavonoid effects on pharmacokinetics of other drugs, 228t–234t nonchiral flavonoids, 197t–217t homoeriodictyol, 33–34 isosakuranetin, 36 taxifolin, 38, 40 Pharmacological activity, 10–45 eriocitrin and eriodictyol, 26–29 antibacterial activity, 26–27 anticancer activity, 28–29 antiinflammatory activity, 27 antimutagenic activity, 29 INDEX antioxidant activity, 27–28 cyclooxygenase-1 and -2 inhibitory activity, 29 gallic acid, 43–45 hesperidin and hesperetin, 12–17 antiadipogenic activity, 17 anticancer activity, 15–16 antifungal, antibacterial, antiviral activity, 12–13 antiinflammatory activity, 13–14 antioxidant activity, 14–15 cyclooxygenase-1 and -2 inhibitory activity, 16–17 estrogenic effect, 17 homoeriodictyol, 32–34 pharmacokinetic studies, 33–34 isosakuranetin, 34–36 pharmacokinetic studies, 36 naringin and naringenin, 17–26 antiadipogenic activity, 23 anticancer activity, 20–22 antifungal, antibacterial, and antiviral activity, 18–19 antigenotoxic properties, 25 antiinflammatory activity, 19–20 antioxidant activity, 20 cardioprotective effects, 23 cyclooxygenase-1 and -2 inhibitory activity, 22–23 effect on cytochrome P450, 23–25 radioprotection, 25–26 phloretin, 29–32 anticancer activity, 31 antiinflammatory activity, 32 antioxidant activity, 31 antithrombotic properties, 32 glucose transport, 30–31 sakuranetin, 43 taxifolin, 36–42 pharmacokinetic studies, 38, 40 Phase I studies chiral flavonoids, 217t–226t flavonoid derivatives, 226t–228t nonchiral flavonoids, 197t–217t Phenolics, structure of, 5, 72 Phenoxodiol clinical pharmacokinetic studies, 202t–203t pharmacokinetics, 237 INDEX Phenylalanine ammonia-lyase (PAL), Phenylalanine in flavonoid synthesis, 6, 7f Phenylpropanoid pathway, 3, 6, 7f Phloretin absorption of, 174 pharmacological activity, 29–32 anticancer activity, 31 antiinflammatory activity, 32 antioxidant activity, 31 antithrombotic properties, 32 glucose transport inhibition, 30–31 sources of, 29 structure of, 29, 29f Phloridzin absorption of, 174 pharmacological activity, 29–32 structure of, 30f Phloroglucinol, in taxifolin metabolism, 41f, 42f Photodiode array detection (PDA), 89–90 Phytochemicals, Phytoestrogens, 261–263, 265 Pinocembrin chiral resolution of, 146, 146f structure of, 124t Pinostrobin chiral resolution of, 147, 147f structure of, 124t Pisatin, 121 Placental transfer of flavonoids, 178 Polyphenols assays for total polyphenolic content, 73–74 dietary intake levels, 9, 73 as glycosides, 73, 83, 93 health benefits of, 9, 11, 73 heterogeneous distribution in plant tissues, 73 as secondary metabolites, sources of, structure, 5, 5f–6f, 72 Polyphenon E, clinical pharmacokinetic studies on, 220t–221t, 233t Polysaccharide columns, 126–128 Poncirin, 36 Porosity, of chromatography column, 84 Pravastatin, 287 335 Preclinical pharmacokinetics, 161–186 Pregnancy, toxicology of flavonoids and, 267–268 autism and, 268 prenatal closure of ductus arteriosus, 267–268 Prenatal closure of ductus arteriosus, maternal flavonoid ingestion and, 267–268 6-prenylnaringenin, chiral resolution of, 148 8-prenylnaringenin ABC transporters and, 295 chiral resolution of, 148 clinical pharmacokinetic studies, 217t structure of, 263f Primary metabolites, Proanthocyanidins sources of, 5, 72 structure of, 6f Probenecid, 301–302 Propolis sensitization, flavonoids and, 266–267 Prunin chiral resolution of, 147 structure of, 124t Pseudohypericin, clinical pharmacokinetic studies on, 205t Puerarin clinical pharmacokinetic studies, 197t pharmacokinetics, 196 Pulmonary artery hypertension, 267 Pycnogenol, 37–38, 40 Quadrupole, 93–94 Quadrupole/time-of-flight (QTOF) MS, 94 Quantitative structure-activity relationship (QSAR) model, 295 Quercetin ABC transporters and, 291, 294t absorption of, 168–171, 169f–170f, 174 BCRP transporter and, 299, 301 biotransformation pathway, 39f clinical pharmacokinetic studies, 203t–206t, 226t, 232t CYP450 inhibition, 303 336 Quercetin (cont’d) distribution of, 176–178 leukemia induction and, 259 medicinal use, 196t metabolism of, 182–183 MRP2 transporter and, 299 P-glycoprotein interaction, 295, 297t, 298 pharmacokinetics, 237 renal toxicity, 256–257 sources of, 289 structure of, 256f in taxifolin metabolism, 41f–42f topoisomerase inhibition, 259 Quercetin-3-glucoside, clinical pharmacokinetic studies on, 204t Quercetin-4-glucoside, clinical pharmacokinetic studies on, 204t Quinic acid, 302f, 303 Racemic flavonoids, 119 Racemization, 10, 120, 133–134 Radioprotection, by naringin and naringenin, 25–26 Renal toxicology of flavonoids, 256–257 Resolution, chromatography, 84–85, 87 Resveratrol See also trans-resveratrol BCRP transporter and, 299 MRP2 transporter and, 299 Reversed-phase chromatography, 82 Reversed-phase high performance liquid chromatography (RP-HPLC) described, 83, 88 mass spectrometry paired with, 89, 94, 96 NMR paired with, 95–96 Reversed-phase liquid chromatography (HP-LC), 83 Rhein, absorption of, 162 Rhodamine 123, 295 Robinetin, 299 Rooibos (Aspalathus linearis), 30 Rutin absorption of, 170–171 biotransformation pathway, 39f discovery of, structure of, 258f INDEX Safety, 249–268 See also Toxicology of flavonoids Sakuranetin chiral resolution of, 147–148 pharmacological activity, 43 structure of, 43f, 124t Saquinavir, 232t, 239, 288, 296 Scutellarin, 174, 291 Secondary metabolites See also specific compounds biosynthetic origins, 3f ecological roles of, 3–4 roles in plants, 72 Selected ion mode (SIM), 92 SGLT transporters, inhibition of, 30 Silybin A clinical pharmacokinetic studies, 201t–202t Silybin B clinical pharmacokinetic studies, 201t–202t Silybin C clinical pharmacokinetic studies, 201t–202t Silybin D clinical pharmacokinetic studies, 201t Silybinin clinical pharmacokinetic studies, 202t Silybin-phosphatidylcholine clinical pharmacokinetic studies, 202t Silymarin BCRP transporter and, 299 clinical pharmacokinetic studies, 201t, 228t–229t CYP 3A4(18) interaction, 196t medicinal use, 196t pharmacokinetics, 196, 237 structure of, 258f Sodium cholate, as chiral mobile phase additive, 131–132 Solubility like dissolves like, 79, 83, 98 Solvent, chromatography, 82 Sophorol, 121 Sources of flavonoids, 8–10 St John’s wort, 284–285, 284f–285f Stereochemistry of flavonoids, 10, 133–136 stability, 119–120 INDEX Stilbenes relationship to other polyphenols, 8f structure, 5f Structure-activity relationship, Synthesis of flavonoids, 4–8, 7f Tacrolimus, St John’s wort effect on, 284, 284f Talinolol, 229t, 238, 285, 286f, 296, 297t Tangeretin, 295 Tannins gallic acid and, 44 hydrolyzable, 44 structure of condensed, 6f Taxifolin biosynthesis of, 38 biotransformation by Clostridium orbiscindens, 42f biotransformation pathway, 39f chiral resolution of, 148 enantiomers, 121 isomerization of, 38 metabolism by Eubacterium ramulus, 41f pharmacokinetic studies, 38, 40 pharmacological activity, 36–42 structure of, 124t Tea consumption and hepatic toxicology, 252–254 Thalidomide, 118 Theaflavin, 121 clinical pharmacokinetic studies, 223t Thearubigins, 121 Theophylline, 233t, 240 Thin layer chromatography (TLC), 87 Thyroid gland, flavonoid exposure and, 264–265, 264t Thyroperoxidase, 264 TNF-α, 19–20, 27 Topoisomerase inhibitors, 259 Topotecan, 299–300, 300t Toxic effects of polyphenols, 73, 107 Toxicology of flavonoids, 249–268 allergy-like responses, 266–267 dermatitis, 267 propolis sensitization, 266–267 blood disorders, 257–259 hemolytic anemia, 257 iron deficiency anemia, 257–259 337 cancer, 259–260 hepatocellular carcinoma, 255–256 leukemia induction, 259 tumor proliferation, 260 endocrine system, 260–265 female reproductive toxicity, 262–263 male reproductive toxicity, 260–262 thyroid, 264–265, 264t gastrointestinal tract, 250–251 colitis, 250–251 diarrhea, 250–251 glaucoma development, 265 hepatic, 251–256 dietary estrogens, 255 flavoxate, 254–255 isoflavones and hepatocellular carcinoma, 255–256 tea consumption and, 252–254 migraines, 265–266 pregnancy and, 267–268 autism and, 268 prenatal closure of ductus arteriosus, 267–268 renal, 256–257 Traditional medicine, 71 Transporters ABC transporters, 290–301, 293t–294t flavonoid modulation of expression, 301 flavonoids as substrates or inhibitors of, 291–292 breast cancer resistance protein (BCRP, ABCG2), 290–292, 293t–294t, 299–301, 300t experimental techniques to study flavonoid interactions with, 292 flavonoid-drug interactions mediated by, 283t, 290–303 multidrug resistance protein (MRP2, ABCC2), 290–291, 293t–294t, 298–299 organic anion transporters (OATs), 301–303, 302f P-glycoprotein (P-gp, ABCB1), 24–25, 31, 284–287, 290–292, 293t–294t, 295–296 CYP450 interaction, 296, 297t, 298 338 trans-resveratrol clinical pharmacokinetic studies, 216t pharmacokinetics, 237 Triple quadrupole (QqQ) MS, 94 Troxerutin clinical pharmacokinetic studies, 206t structure of, 258f Tumor proliferation, 260 Two-dimensional thin-layer chromatography (2D-TLC), 87 Ultrahigh performance liquid chromatography (UHPLC), 85, 108 Ultraviolet-visible (UV-VIS) detection, 89–90 United States Department of Agriculture (USDA), 282 Urethral hypospadias, 262 INDEX Vanillic acid, 72 Vascular endothelial growth factor (VEGF), 22 Verapamil, 233t, 234t, 240, 295, 297t, 298 Vestitone, 121 Vinblastine, 295–296, 298 Vincristine, 295 “Vitamin P,” World Health Organization (WHO), 11, 73 Xenobiotics, 10, 44 Yerba santa (Eriodictyon glutinosum), 32 .. .FLAVONOID PHARMACOKINETICS Methods of Analysis, Preclinical and Clinical Pharmacokinetics, Safety, and Toxicology Edited by NEAL M DAVIES Faculty of Pharmacy University of Manitoba... dollars spent on drug Flavonoid Pharmacokinetics: Methods of Analysis, Preclinical and Clinical Pharmacokinetics, Safety, and Toxicology, First Edition Edited by Neal M Davies and Jaime A đez © 2013... variety of fields Hence, the objective of this book is to provide the framework for fundamental concepts and contemporary practice of methods of analysis for achiral and chiral flavonoids, preclinical