S ECOND E DITION I NTERACTIONS H ANDBOOKOF D RUG -N UTRIENT

(1)

(2)

H ^{ANDBOOK OF} D ^RUG -N ^UTRIENT I NTERACTIONS

S ^ECOND E ^DITION

(3)

N UTRITION AND H ^EALTH

Adrianne Bendich, PhD, FACN, S

^ERIES

E

^DITOR

For other titles published in this series, go to www.springer.com/series/7659

(4)

H ^{ANDBOOK OF}

D ^RUG -N ^UTRIENT I NTERACTIONS

Second Edition

Edited by

J ^OSEPH I. B ^OULLATA , ^P ^harm ^D

Associate Professor of Pharmacology & Therapeutics, University of Pennsylvania, School of Nursing,

Philadelphia, PA, USA

and

V ^INCENT T. A ^RMENTI , ^MD , ^P ^h ^D

Professor of Surgery,

Professor of Pathology, Anatomy and Cell Biology, Thomas Jefferson University,

Philadelphia, PA, USA

Foreword by

G ^IL H ^ARDY ^{PhD, FRSC}

Professor of Pharmaceutical Nutrition,

Faculty of Medical and Health Sciences, University of Auckland,

Auckland, New Zealand

(5)

Associate Professor of Pharmacology &

Therapeutics

University of Pennsylvania School of Nursing 418 Curie Blvd.

Philadelphia PA 19104 USA

Professor of Surgery

Professor of Pathology, Anatomy, and Cell Biology

Thomas Jefferson University 1025 Walnut St., Suite 605 Philadelphia, PA 19107 USA

Series Editor

Adrianne Bendich, PhD

GlaxoSmithKline Consumer Healthcare Parsippany, NJ

ISBN 978-1-60327-363-3 e-ISBN 978-1-60327-362-6 DOI 10.1007/978-1-60327-362-6

Library of Congress Control Number: 2009930756

#Humana Press, a part of Springer ScienceþBusiness Media, LLC 2010

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer ScienceþBusiness Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.

The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper springer.com

(6)

Dedication

This book is dedicated to our families who accepted with good humor the time required to work on the project.

Joseph I. Boullata and Vincent T. Armenti

v

(7)

We acknowledge the strong commitment of each of our authors to this project.

Additionally, the ongoing support and encouragement from Adrianne Bendich for this topic and project has been invaluable. Finally, we acknowledge Richard Hruska and his staff at Humana Press for the administrative support of the project.

Joseph I. Boullata and Vincent T. Armenti

vii

(8)

Series Editor Introduction

The Nutrition and Health Series of books have, as an overriding mission, to provide health professionals with texts that are considered essential because each includes (1) a synthesis of the state of the science; (2) timely, in-depth reviews by the leading researchers in their respective fields; (3) extensive, up-to-date fully annotated reference lists; (4) a detailed index; (5) relevant tables and figures; (6) identification of paradigm shifts and the consequences; (7) virtually no overlap of information between chapters, but targeted, interchapter referrals; (8) suggestions of areas for future research; and (9) balanced, data-driven answers to patient/health professionals questions that are based upon the totality of evidence rather than the findings of any single study.

The goal of the series is to develop volumes that are adopted as the standard text in each area of nutritional sciences that the volume reviews. Evidence of the success of the series is the publication of second, third, and even fourth editions of more than half of the volumes published since the Nutrition and Health Series was initiated in 1997. The series volumes that are considered for second and subsequent editions have clearly demonstrated their value to health professionals. Second editions provide readers with updated information as well as new chapters that contain relevant up-to-date information. Each editor of new and updated volumes has the potential to examine a chosen area with a broad perspective, both in subject matter as well as in the choice of chapter authors. The international perspective, especially with regard to public health initiatives, is emphasized where appropriate.

The editors, whose trainings are both research and practice oriented, have the opportunity to develop a primary objective for their book, define the scope and focus, and then invite the leading authorities from around the world to be part of their initiative. The authors are encouraged to provide an overview of the field, discuss their own research, and relate the research findings to potential human health consequences. Because each book is developed de novo, the chapters are coordinated so that the resulting volume imparts greater knowledge than the sum of the information contained in the individual chapters.

‘‘Handbook of Drug–Nutrient Interactions – Second Edition’’ edited by Joseph I.

Boullata and Vincent T. Armenti fully exemplifies the Nutrition and Health Series’

goals. This volume is very timely as about 80% of Americans consume at least one drug – defined as a pharmaceutically active agent – regularly. Moreover, the fastest growing population in the United States as well as globally is that over 60 years of age and especially the oldest-old, those over 80 years of age, and drug use increases

ix

(9)

with increasing age. Additionally, the aged are at greatest risk for both deficiencies as well as overconsumption of certain nutrients that could be further exacerbated by drug–nutrient interactions. The editors clearly understand the seriousness of the issue of drug–nutrient interactions. They have stated that ‘‘In the care of patients, both drug therapy and nutritional therapy are critical. The potential for drugs and nutrients to interact with each other is significant, but unrecognized by many clinicians. These interactions may result in therapeutic failure or adverse effects of the drug, or alterations in the nutritional status of the patient – in either case impacting the patient’s outcome.’’

This important handbook presents a timely review of the latest science concerning drug–nutrient interactions as well as practical, data-driven guidance for the management of at-risk populations exposed to therapeutic interventions. The over- arching goal of the editors is to provide fully referenced information to health professionals so they may enhance the nutritional welfare and overall health of clients and patients who may not have been aware of potential unexpected drug–

nutrient interactions. This excellent, up-to-date handbook will add great value to the practicing health professional as well as those professionals and students who have an interest in the latest information on the science behind the interactions of nutritional status and drug metabolism and vice versa, the changes in these interactions during the lifespan, and the potential for drug–nutrient interactions, either beneficial or harmful, to modulate the effects of chronic diseases and conditions that are widely seen in the majority of patient populations.

Drs. Boullata and Armenti are internationally recognized leaders in the field of pharmacology and nutrition with particular expertise in clinical approaches to effective management of drug/disease/diet interactions. Dr. Boullata is a recognized leader in the field of nutritional pharmacology, and Dr. Armenti is a transplant surgeon, and they serve as professors of Pharmacology and Therapeutics and of Pathology, Anatomy and Cell Biology, and Surgery respectively. Both editors are excellent communicators and they have worked tirelessly to develop the second edition of their handbook that is already established as the benchmark in the field of clinical nutrition. This volume continues to include extensive, in-depth chapters covering the most important aspects of the complex interactions between dietary components and nutrient requirements and their impact on drug absorption, distribution, and elimination. Drugs used in the treatment of chronic diseases as well as the acute conditions in both men and women are reviewed with the emphasis on the effects of these therapies on nutritional status.

The introductory chapters provide readers with the basics of the complexities involved in drug disposition as the drugs move from the absorptive surface to the blood and then to target organs and organelles in the liver and other organs that contain drug-metabolizing enzymes. Detailed information about dosing and potential drug/nutrient interactions is tabulated. Additionally, a new chapter on drug transporters including informative tables concerning their location and the molecules that are transported into and out of cells has been added to the handbook.

Drug-metabolizing enzymes have complex functions. The next chapter describes the actions of many of the 57 functional CYP enzymes in the liver and cites over 300 references. Finally, to assure that all readers have a basic understanding of the

(10)

human gastrointestinal tract, the last chapter in this part describes the effects of food movements in the GI tract, the release of enzymes and signaling molecules in the mouth through the anus, and the absorption of food in the intestine. Thus, in the first part of the volume, the reader is provided with valuable information about the basics of drug as well as nutrient metabolism and a review of the drug classes and their expected disposition within the body and transport, enzymatic conversions, and potential interactions with dietary constituents.

Part II reviews the influence of nutritional status on drug disposition and effects.

Two chapters examine the effects of either under- or over-nutrition (obesity) on drug disposition and their effects. Both comprehensive chapters review relevant classes of drugs that can be most affected by low body weight and obesity or overweight conditions. As more than half the US population is either overweight or obese, this chapter is of great importance when considering drug doses for efficacy.

Part III contains seven chapters that examine the influence of foods, nutrients, and supplements on drug disposition. Co-administration of a drug with a meal can have significant effects on the drug’s pharmacokinetics and is especially critical if the drug has a relatively narrow window of efficacy. Specific information about the negative effects of meals on absorption of protease inhibitors as well as the benefits of modified-release oral dosage forms is presented. Practical examples, clinical study designs, and tables describing medications to be taken with and without food are included to better assure that the effect of food on drug efficacy is under- stood by the health provider. Specific foods and food components have been found to have significant effects on drug absorption and effectiveness. Macronutrients including fat and protein, cruciferous vegetables, grapefruit juice, caffeine, alcohol, vitamins, and certain herbs as well as food preparation, such as charcoal broiling, can all affect drug disposition and are reviewed. Because the effect of grapefruit juice and other juices can affect many drugs, this topic that includes over 200 references, is presented in detail in its own chapter. Certain drugs are poorly absorbed, but absorption is best when taken with food and/or specific nutrients.

Certain adverse effects of drugs, such as competing with essential nutrients, can be blunted with dietary changes. These beneficial drug–nutrient interactions are described for the relevant drug classes in the next chapter. Use of dietary supplements has increased dramatically in the United States over the past decade and the variety of supplements and their regulation as well as effects on drug disposition definitely deserved its own chapter. This chapter concentrates on the herbal dietary supplements with the greatest amount of scientific data and includes discussions of garlic, valerian, kava, ginkgo, St. John’s Wort, glucosamine/chondroitin, and gin- seng. The author has included discussion points as well as responses for the educator or health provider. The next two chapters examine the serious conditions that are associated with enteral and parenteral nutrition and the effects of these nutrient delivery systems to patients who are very often taking one or more medications. Enteral feeding adds complexity to drug pharmacokinetics as co-administration via the tube can result in physical inactivation of the drug and/or modifications to certain nutrients because of exposure to the drug. There is a detailed description of the types of interactions possible between drug and enteral nutrition feeding as well as effects of site of

Series Editor Introduction xi

(11)

administration, types of enteral formulas and their nutritional components and importantly, a comprehensive tabulation, in 12 tables, of practice guidelines and data on the drugs and their components, such as sorbitol, that may require careful administration to the tube fed patient. Intravenous delivery of nutrients to patients is also obviously complex and challenged further by drug administration. The compatibility and stability of both drug and nutrients are discussed at length, and practice guidelines are provided, as well as 10 informative tables.

Part IV describes the influence of medications on nutritional status and nutrient distribution and effects, and it contains five chapters. The first chapter examines the effects of specific drugs on weight (gain or loss), taste changes, altered GI motility, and metabolic effects, including nutrient depletion. Detailed tables list drugs associated with alterations in taste as well as medications that affect vitamin and mineral status. Because cardiovascular disease is the number one killer in developed nations, and the number and classes of drugs used to treat CVD increase annually, a separate chapter is devoted to the influence of CVD medications on nutritional status. Ten classes of CVD drugs are described in detail with emphasis on their overall effects as well as specific effects of the most commonly used drugs on metabolism and nutritional status. The chapter contains over 200 citations. Drugs that treat neuro- logical illnesses, especially epilepsy, often adversely affect certain B vitamin levels and several are classified as anti-folates. There are also adverse effects on bone and vitamin D status with many of these drugs. Many of the drugs are teratogenic in part a result of their effects on essential nutrients. Parkinsonism, stroke and major brain injury treatments, and nutritional consequences are outlined as well. This informative chapter contains clinical discussions and recommendations. The next chapter provides more in-depth analysis of the physiological roles of folic acid and the effects of drugs that adversely affect folate status. There is also a very useful patient handout that can be used when prescribing an anti-folate such as those included in the comprehensive tables of this chapter. The final chapter in this part reviews the potential effects of drugs on mineral status and includes discussions of sodium, potassium, phosphorus, magnesium, iron, copper, zinc, chromium, sele- nium, fluoride, iodine, and relevant information on several other trace minerals that are summarized in key tables. The potential for alcohol, illicit drugs, and cigarette smoking to affect mineral status is included as well.

Of particular relevance to clinicians are the chapters in Part V that examine drug nutrient interactions by life stages. Drug–nutrient interactions in infancy and childhood are reviewed with emphasis on the determination of correct dosage levels and dosage forms for the young child. As with the chapter on enteral nutrition, the physical effect of the drug when in contact with infant formula or foods is an important aspect of avoiding adverse reactions. Herb–drug interactions are also included as the use of these products in children has increased in recent years. This chapter contains 13 tables with relevant practice information for the health-care provider. The next chapter in this part reviews drug–nutrient interactions during pregnancy and lactation. Drug effects on the embryo and fetus, placental transfer of drugs, expansion of plasma volume, increases in estrogen and other hormones that can alter metabolic rate, and alterations in renal function, drug effects on appetite and nutrient absorption, drug effects on milk production, drug transfer to breast

(12)

milk, infant exposure are reviewed, and useful tabulations including information sources on risk of drug use in pregnancy and lactation are provided. The final chapter in this part discusses drug–nutrient interaction in the elderly. This chapter is especially valuable as about one-third of all prescriptions are given to elderly patients who actually make up about 12% of the US population. Drug–nutrient interactions may be of increased risk to the elderly because of the age-related decreases in nutrient absorption, metabolism, and excretion independent of drug use. The chapter provides important insights to help the health provider avoid the real potential for drug-induced adverse health outcomes in elderly patients taking a single or more likely multiple drugs daily. Moreover, the 5 comprehensive tables and more than 250 references provide additional resources to the reader.

The final part of the volume looks at drug–nutrient interactions in individuals who have either chronic diseases or special needs for certain classes of drugs. The chapter on cancer patients is particularly sensitive to the potential for the older as well as newer classes of drugs to affect the precarious health balance in these patients. Tables in the chapter review potential specific drug-induced changes in nutritional status in the cancer patient. Transplant patients also have unique needs, and this chapter provides details about the current antibodies used for transplant induction immediately following transplant and effects on the GI tract – specific issues with transplant of the kidney, liver, pancreas, lung, heart, and small bowel – and concentrates on the nutrient requirements for patients post-transplant. Two chapters examine the effects of the major diseases of the immune system and the effects of chronic infections on nutritional status and then review the nutritional effects of the drugs used to treat these diseases. New and older classes of drugs for HIV and tuberculosis have different effects on the GI tract and nutritional status, and these effects are discussed. There is a comprehensive overview of the human immune system, the effects of specific essential nutrient deficiencies, the effects of major diseases of the immune system with a concentration on autoimmune diseases, including rheumatoid arthritis, diabetes, and lupus, the drugs used in treatment and the interactions of the disease, drug, and nutritional status. Also, there is an in- depth discussion of the importance of pre- and probiotics especially in reference to autoimmune diseases of the GI tract. The seven extensive tables compile information on the major drugs to treat autoimmune diseases as well as infections; the chapter contains more than 300 references.

Drug–nutrient interactions are complex, yet the editors and authors have provided chapters that balance the most technical information with practical discussions of the importance for clients and patients as well as graduate and medical students, health professionals, and academicians. Hallmarks of the chapters include chapter outlines that reflect the content, discussion questions that can guide the reader to the critical areas covered in each chapter, complete definitions of terms with the abbreviation fully defined, and consistent use of terms between chapters.

There are over 120 relevant tables, graphs, and figures as well as more than 3800 up- to-date references; all of the 26 chapters include a conclusion section that provides the highlights of major findings. The volume contains a highly annotated index, and within chapters, readers are referred to relevant information in other chapters.

Series Editor Introduction xiii

(13)

The editors of this comprehensive volume have chosen 42 of the most well- recognized and respected authors who are internationally distinguished researchers, clinicians, and epidemiologists who provide a broad foundation for understanding the role nutritional status, dietary intakes, route of drug administration, life stages of patients, and also disease state and multiple drug use in the background of genetic and clinical aspects of nutritional and therapeutic management of these interactions. Recommendations and practice guidelines are included at the end of relevant chapters.

In conclusion, ‘‘Handbook of Drug–Nutrient Interactions – Second Edition’’ edited by Joseph I. Boullata and Vincent T. Armenti provides health professionals in many areas of research and practice with the most up-to-date, well-referenced volume on the importance of the consideration of drug–nutrient interactions for determining the potential for optimal responses to the medicines that are provided to patients.

This volume will serve the reader as the benchmark in this complex area of inter- relationships between nutritional status, physiological functioning of organ systems, disease status, age, sex, route of administration, and duration and strength of dosage of the myriad of prescription drugs currently available for treatment. More- over, the interactions between genetic and environmental factors and the numerous co-morbidities seen especially in the aging population are clearly delineated so that students as well as practitioners can better understand the complexities of these interactions. Drs. Boullata and Armenti are applauded for their efforts to develop the most authoritative resource in the field to date, and this excellent text is a very welcome addition to the Nutrition and Health Series.

Adrianne Bendich, PhD, FACN

(14)

Foreword

Interactions between drugs and nutrients can cause an alteration of the pharmacokinetics and pharmacodynamics of a drug or pharmaconutrient that compromises nutritional status as a result of their interplay. This can be either harmful or beneficial. Common adverse events include nutritional deficiencies, drug toxicity, loss of therapeutic efficacy or disease control, and unwanted physiological changes.

The working definition of drug–nutrient interactions used in this excellent handbook is broader than often described elsewhere. It is defined as an interaction resulting from a physical, chemical, physiological, or pathophysiological relationship between a drug and a nutrient, multiple nutrients, food in general, or nutritional status. The clinical consequences of an interaction are related to alterations in the disposition and effect of the drug or nutrient.

Rational drug or nutrition therapy requires a management plan based on the correct interpretation of the symptoms and knowledge of the physiological action of the remedy. The physician must therefore make the correct diagnosis and understand the pathophysiology of the disorder before deciding on drug treatment. They should also know enough about the drugs, or receive appropriate pharmaceutical and nutritional advice to select the right drug and administer it in the right dose for the right length of time by the most appropriate route. In addition, the physician must be aware of the potential for both drug–drug and drug–nutrient interactions within the environmental, genetic, and disease-related context.

Pharmaceuticals and pharmaconutrients undergo metabolism through the action of a diverse group of enzymes. The activity of these enzymes is affected by both diet and genotype, and this may be relevant to disease risk, response to diet, and also to optimization of drug dosage in a clinical setting. Dietary factors influence the expression and function of these genes and are likely to have flow- on effects on both drug elimination and disease pathogenesis. Polymorphisms in genes are also critical in determining an individual response to either foods or drugs. Given the number of nutrients and dietary components affecting the immune response, a combined approach involving drugs and pharmaconutrients may become increasingly important in future clinical strategies against illness and disease.

These are exciting times for the pharmaceutical and nutritional sciences. Within the space of only 30 years, I have been privileged to participate in and observe the American Society for Parenteral and Enteral Nutrition (ASPEN) metamorphose from a group of dedicated Americans pioneering advances in nutrition support into

xv

(15)

a widely respected multidisciplinary international scientific society promoting optimal nutrition therapy and pharmaconutrition. These new paradigms encompass the same scientific advances in immunology, molecular biology, nutrigenomics, and substrate metabolism that are being investigated in the development of new pharmaceuticals for therapeutic interventions into the major debilitating diseases of the 21st century. Providing optimal nutrition therapy is as vital to patient outcome as prescribing the correct drug, but as our knowledge of clinical nutrition has expanded, so too have the complexities of the nutrition and drug therapies that patients are prescribed. Incorporating drug–nutrient interaction investigations into new drug development programs may eventually become important for obtaining regulatory approval as well as for improving patient outcome.

The goal of this second edition of the Handbook of Drug–Nutrient Interactions is to provide an updated compilation of information on drug–nutrient interactions that will enable health-care providers to better manage their patients. This textbook is intended for use by physicians, pharmacists, nurses, dietitians, and others involved in clinical practice with patients using medication as part of their management regimen. This latest edition, with much new data, will meet its goal by providing both the scientific basis and the clinical relevance with appropriate recommendations for many interactions.

As a researcher and teacher, I particularly appreciate the accessibility and logical simplicity of this reference text which falls naturally into a series of discrete parts:

the introductory section provides a basic introduction to drug–nutrient interactions, drug and nutrient dispositions, transporters, and their metabolizing enzymes. This is followed by an important part describing the influence of the extremes of nutritional status, i.e., malnutrition and obesity, on drug disposition and effect. Then a comprehensive part provides a series of chapters on the influence of food and food supplements on drug absorption; fruit juice interactions with medicines; positive drug–nutrient interactions; and enteral and parenteral nutrition. A separate part addresses drugs which influence nutritional status, and a further series of related chapters focus on the role of specific micro- and macro-nutrients in various life stages with particular attention to interactions in infancy and childhood; pregnancy and lactation; and very importantly drug–nutrient interactions in the elderly.

Between 10% and 12% of the population in most Western countries is over the age of 65, and it is projected that one in five Americans will be elderly by 2030.

However, this relatively small percentage of patients already use more than a third of all medicines prescribed. Moreover, polypharmacy or multiple drug therapy is common in older people. Malnutrition is also more prevalent in the elderly and can be associated with impaired food metabolism, affecting the pharmacokinetics and/

or pharmacodynamics of drugs resulting in new drug–nutrient or metabolite interactions.

The editors, Joseph Boullata, PharmD, and Vincent Armenti, MD, PhD, have performed an outstanding service to clinical pharmacology and pharmaconutrition by bringing together a multi-disciplinary group of authors for the second edition of this handbook. The authors, many of whom I am acquainted with through ASPEN, are experts in their designated area. Although predominantly based in North America, they comprise pharmacists, physicians, dietitians, nurses, and

(16)

nutritionists, who successfully ensure the text is written in a clear, direct, and authoritative style to appeal to their peers throughout the international health- care community. Their expertise and experience provide not only a comprehensive up-to-date text for the total management of patients on drug and/or nutrition therapy but also an insight into the recent developments in drug–nutrition interactions which will act as a reliable reference for clinicians and students for many years to come.

Gil Hardy, PhD, FRSC

Foreword xvii

(17)

In the 5 years since publication of the first edition of the Handbook of Drug–

Nutrient Interactions, new perspectives have emerged and new data have been generated on the subject matter. We have attempted to capture this in the current chapters which have all been revised or are completely new to this edition.

This book is intended for use by physicians, pharmacists, nurses, dietitians, and others whether in training, in clinical practice, in academia, or in research. The book has retained the goals of the previous edition which include improving recognition and management of drug–nutrient interactions. The topic of drug–nutrient interactions is significant for clinicians and researchers alike. For clinicians in particular, the book offers a guide for understanding, identifying or predicting, and ultimately preventing or managing drug–nutrient interactions to optimize patient care. The book provides a scientific look behind many drug–nutrient interactions, examines their relevance, offers recommendations, and suggests research questions to be explored. Although not inclusive of every potential interaction, we hope that the breadth and depth of the book will challenge readers to actively engage in improving the quantity and quality of data in the field. This will help increase the profile of drug–nutrient interactions to that comparable with drug–drug interactions in the care of patients.

We appreciate the dedication of our many authors and those who have provided encouraging comments in the continued development of this reference work. While we welcome new authors who have contributed their expertise and perspective to the book, we remain indebted to the authors from the first edition who set the book in motion, many of whom have worked to revise and update their chapters for this second edition. We were, however, saddened by the loss of Mary Berg, who contributed the original chapter on the Effects of Antiepileptics on Nutritional Status, and by the loss of David Fleisher, who helped prepare the chapter on Drug Absorption with Food. Each was a leader in the respective subject matter of their chapter and will be greatly missed. As we look forward to the ongoing emergence of new information concerning drug–nutrient interactions, we continue to welcome comments from readers that will improve this book and the care of patients.

Joseph I. Boullata, PharmD, BCNSP Vincent T. Armenti, MD, PhD

xix

(18)

I ^A ^PPROACHING ^D ^RUG ^–N ^UTRIENT

I NTERACTIONS

(25)

(26)

1 An Introduction to Drug–Nutrient Interactions

Joseph I. Boullata

Objectives

Define the term drug–nutrient interaction in its broadest sense.

Describe the classification of drug–nutrient interactions with examples of each.

List possible approaches for identifying, preventing, and managing drug–nutrient interactions.

Key Words: Classification; dietary supplement; drug-nutrient; drug-food; interaction;

regulation

1. SCOPE OF THE ISSUE

Advances in the pharmaceutical sciences and nutritional sciences continue unabated. Their application to patient care are expected to generate clinical benefits.

Currently there are thousands of drug products commercially available, and approxi- mately 80% of Americans take at least one pharmacologically active agent on a regular basis (1). The sales of pharmaceuticals continue to rise with figures suggesting global sales of over 700 billion U.S. dollars in 2007, nearly 290 billion dollars of that in the United States alone with just over 3.8 trillion prescriptions dispensed (2).

Prescription drug use and spending is projected to accelerate significantly despite economic instability (3).

The use of food and nutritional products is more difficult to quantify, although obviously widespread. The availability of food for daily consumption on a global scale averages out to about 2800 kcal per individual (4). Data in the United States suggest mean per capita consumption of 2157 kcal and 81.8 g protein daily (5). Of course actual nutrient consumption is influenced by many factors from availability, cost, and economics to beliefs and preferences, cultural traditions, and geography (4). Environmental factors further influence the nutritional status of populations and individuals.

From: Handbook of Drug-Nutrient Interactions

Edited by: J.I. Boullata, V.T. Armenti, DOI 10.1007/978-1-60327-362-6_1 Ó Humana Press, a part of Springer ScienceþBusiness Media, LLC 2010

3

(27)

Given the widespread use of medication combined with the variability in nutritional status, dietary habits, and food composition, the number of potential interactions between medication and nutrition is overwhelming. Although the number of interactions and permutations may seem infinite and the proportion that may be clinically significant is not clear, scientists and clinicians should not discount the relevance of drug–nutrient interactions to either product development or clinical practice. The prevalence rate for hospital admissions associated with adverse drug reactions in adults ranges from 3.9% to 13.3% (6). The proportion of these that may be drug–nutrient interactions is not known. An ongoing drawback that remains is the absence of properly designed and conducted epidemiologic studies of drug–nutrient interactions (7). This is in large part due to limited or unclear definitions in the literature.

2. DEFINITIONS

The working definition of drug–nutrient interactions used throughout this book is broader than often described elsewhere. It is defined as an interaction resulting from a physical, chemical, physiologic, or pathophysiologic relationship between a drug and a nutrient, multiple nutrients, food in general, or nutritional status (8). An interaction is considered to be clinically significant if it alters pharmacotherapeutic response or compromises nutritional status. The clinical consequences of an interaction are related to alterations in the disposition and effect of the drug or nutrient. The term disposition refers to the absorption, distribution, and elimination of a drug or nutrient which can involve physiologic transporters and metabolizing enzymes. And the term effect refers to the physiologic action of a drug or nutrient at the level of cellular or subcellular targets. Drug–nutrient interactions can influence health outcomes particularly in vulnerable populations (9).

Several factors may influence the risk for developing a clinically significant drug–nutrient interaction. These include patients with chronic disease who use multiple medications, particularly those drugs with a narrow therapeutic index. The prevalence of medication use in the elderly is widely recognized with consequences that include greater adverse drug effects and drug–nutrient interactions (10). Indivi- duals at either end of the age spectrum, as well as those with genetic variants in drug transporters, enzymes, or receptors, impaired organ function, or poor nutritional status, also have heightened susceptibility to interactions. In this sense, poor nutritional status refers to altered body composition or function resulting from any imbalance between an individual’s nutrient requirements and intake – whether the imbalance is due to poor dietary intake or altered nutrient disposition.

Drug–nutrient interactions can be viewed in terms of pharmacokinetics and pharmacodynamics. Drugs and nutrients can influence signal transduction pathways that ultimately impact on drug-metabolizing enzymes and transporters through receptor-mediated gene expression (11,12). The more that is known about drugs serving as substrate, inducer, or inhibitor of various transporters and enzymes in various tissues, the closer that direct or indirect interaction with nutrients that influence these same proteins can be determined or predicted. Pharmacokinetic interactions can involve enzymes and transporters that are implicated in drug absorption, distribution, or elimination. Pharmacokinetic interactions are best

(28)

defined by changes in drug or nutrient parameters (e.g., bioavailability, volume of distribution, clearance). Pharmacodynamic interactions involve the clinical effect of a drug or physiologic effect of a nutrient. Qualitative or quantitative measures of drug action or of nutritional status help to define pharmacodynamic interactions.

3. PERSPECTIVES 3.1. Historic

For years, the potential for interactions between drug therapy and nutrition was barely mentioned in reference works that probably should have discussed the subject (13–15). This began to change with publication of classic findings such as the influence of vitamin C deficiency on barbiturate action (16), the influence of iron on tetracycline absorption (17), the influence of isonaizid on vitamin B₆metabolism (18), as well as reviews on the impact of malnutrition on drug disposition (19), the effect of food on drug absorption (20), and the influence of drugs on nutrient disposition (21). This historic perspective has been described in further detail (22).

The increased awareness of drug–nutrient interactions has yet to be fully translated and integrated into the general knowledge of clinicians, scientists, and regulators who in turn have the ability to make meaningful contributions to the subject.

3.2. Clinician

Drug interactions contribute to adverse drug effects and can lead to withdrawal of approved drugs from the market (23). Interactions between one drug and another have long been recognized as influencing patient outcomes through altered drug disposition and effect. Drug–nutrient interactions have been considered less significant than drug–drug interactions with the former often limited in scope to the dosing of an oral drug in relation to a meal or perhaps the effect of a drug on body weight or serum glucose and electrolyte concentrations. Surveys suggest poor knowledge of common drug–nutrient interactions among health-care providers, with few offering counseling to most of their patients on the topic (24,25). Some clinicians may recognize specific interactions as individual pieces of information – for example, interactions that interfere with drug absorption (e.g., calcium-containing food products and tetracycline or ciprofloxacin) or other well-described classic interactions (e.g., tyramine-containing foods with monoamine oxidase inhibitors) – but not realize that each can fit into a larger classification system. Generally, product information is not considered an optimal resource for information on drug–nutrient interactions (26). In order for clinicians to recognize, identify, prevent, or manage drug–nutrient interactions that have the potential to influence patient outcome, a more systematic approach to this area of therapeutics is necessary. Such an approach may also be of value to product development.

3.3. Scientist

The science of describing drug–drug interactions has evolved significantly (27).

Drug–drug interactions are widely recognized, identified, and managed in practice.

The evaluation of drug–drug interactions is also inherent to the drug development process as reflected in guidance documents for industry. Unfortunately, the same

Chapter 1 / An Introduction to Drug–Nutrient Interactions 5

(29)

may not be said for drug–nutrient interactions yet. The same attention given to the potential for pharmaceutical, pharmacokinetic, or pharmacodynamic drug–drug interactions needs to be afforded to the study of drug–nutrient interactions (8).

Drug–nutrient interactions beyond meal effects need to be considered in new drug evaluations as well (23). In the meantime, clinicians should have access to interaction information that allows safe treatment approaches. Because of limited clinical drug–nutrient interaction data generated as part of the drug development process, much will have to be explored in postmarketing observational studies, or from individual case reports, with subsequent mechanistic investigations and descriptions when novel interactions are identified.

3.4. Regulatory

The philosophic approach of the U.S. Food and Drug Administration (FDA) within the framework of the Federal Food, Drug and Cosmetic Act has been to reserve enforcement only when regulatory violations are identified; otherwise, they encourage industry self-regulation (28). As part of that encouragement, the FDA provides guidance for industry on emerging aspects of drug development, approval, and safety. Although the FDA still does not require an evaluation of drug–nutrient interactions in its guidance process for drug development, there may be room for its consideration within the drug interaction guidance (29,30). A good guidance practice document, specific for drug–nutrient interactions, may be less likely to be considered, although the FDA could identify issues and determine whether a working group needs to be developed. Among other features, a discussion of pharmacokinetic and pharmacodynamic endpoints as well as evaluating the degree of change following an interaction (enzyme or transporter) is equally relevant to drug–nutrient interactions (29). Although these can be used to guide characterization of new molecular entities in the drug development process, they can also be applied to a reevaluation of high-risk drugs already in use. New data generated for the latter will require revision to the labeling. Any identification of potential interactions based on early in vitro study helps determine the necessity of subsequent in vivo evaluation.

Currently available decision trees can be modified to address drug–nutrient interactions, as can existing criteria (e.g., identifying inhibitor or inducer substrate) (29). For example, an enzyme inhibitor would have to result in a twofold increase in the area under the concentration–time curve (AUC) to be considered ‘‘moderate’’ in its effect.

4. CLASSIFICATION AND DESCRIPTIONS

Based on the working definition provided above, drug–nutrient interactions can be classified into one of five broad categories (Table 1) (8). The many types of drug–nutrient interactions can thus be categorized with each having an identified precipitating factorand an object of the interaction. In some cases, the drug is the precipitating factor (i.e., causing changes to nutritional status), while in others the drug is the object of the interaction (i.e., changes in drug disposition or effect result from a nutrient, food, or nutritional status). Drug–nutrient interactions are clinically important if the precipitating factor produces significant change in the

(30)

object of the interaction. Interactions that need to be totally avoided are not common; instead close monitoring with modification to the dosing schedules is usually all that is necessary. The nature of any physicochemical or physiologic interaction and its mechanism may be further classified to help in predicting and preventing their occurrence (Table 2) (31). Mechanisms of an interaction relate to the physicochemical attributes of the medication and of the food or nutrient, within the environmental matrix (e.g., the feeding tube or the patient). The consequence of an interaction (altered disposition of a drug or nutrient) is linked to its location. For example, at the gastrointestinal mucosa, an influence on membrane transporters and/or metabolizing enzymes can alter the bioavailability of a drug or nutrient.

Another dimension to be considered is that physiologic manifestations of a Table 1

Classification of Drug–Nutrient Interactions (8)

Precipitating factor

Object of the

interaction Potential consequence^y

Nutritional status Drug Treatment failure or

drug toxicity

Food or food component Drug Treatment failure or

drug toxicity Specific nutrient or other dietary

supplement ingredient

Drug Treatment failure or drug toxicity

Drug Nutritional

status

Altered nutritional status

Drug Specific nutrient Altered nutrient status

ySee text for specific examples.

Table 2

Location and Mechanisms of Drug–Nutrient Interactions (31)

Site of interaction Consequence^y Mechanism of interaction In drug (or nutrient)

delivery device or gastrointestinal lumen

Reduced

bioavailability

Physicochemical reaction and inactivation

Gastrointestinal mucosa Altered

bioavailability

Altered transporter and/or enzyme function

Systemic circulation or tissues

Altered distribution/

effect

Altered transporter, enzyme, or other physiologic function Organs of excretion Altered clearance Antagonism, impairment, or

modulation of elimination

yConsequence to the drug and/or nutrient.

(31)

drug–nutrient interaction may differ based on gene polymorphism (e.g., methotrex- ate and folic acid) (32,33). The role of polymorphisms in nuclear receptors, metabolizing enzymes, and other proteins needs to be taken into account (34). A brief description of each drug–nutrient interaction category follows with select examples.

4.1. Nutritional Status Influences Drug Disposition

Pharmacokinetic and pharmacodynamic data in special patient populations usually focus on those with renal impairment, hepatic dysfunction, or unique life- stage attributes. Drug disposition is much less frequently assessed based on nutritional status (e.g., protein-calorie malnutrition, obesity, micronutrient deficits), although the influence on drug metabolism has been recognized (35–37). The nutritional status of subjects in clinical drug trials has not always been well described. Drug distribution and clearance are the pharmacokinetic parameters most likely to be influenced by malnutrition. Nutritional status may modify susceptibility to other chemical exposures as well (9). Therapeutic effectiveness or risk for toxicity can be altered by the degree of malnutrition (38).

Reviews on drug class-specific considerations in obesity are welcome, given the ongoing epidemic. Much attention has been paid to antimicrobials in obesity, in view of the clinical repercussions of not accounting for altered drug distribution or clearance (39). This has also been suggested in the case of antibiotics used in undernourished children (40).

During treatment for cellulitis with piperacillin-tazobactam 3.375 g q4h intravenously in a morbidly obese patient (body mass index [BMI] 50 kg/m²), pharmacokinetic sampling revealed an altered volume of distribution (Vd) (0.33 L/kg) and clearance (Cl) (27 L/h) for piperacillin, compared with normal values (41). This indicates that the dosing of piperacillin can be based on total body weight, especially if dealing with a Pseudomnas aeruginosa minimum inhibitory concentration (MIC) > 8 mg/L (41).

An area of particular concern is the preoperative dosing of antimicrobials to prevent postoperative infection in obese patients undergoing surgical procedures.

A 1 g dose of cefazolin as antibiotic prophylaxis for surgery in patients with BMI

> 40 kg/m² resulted in serum drug concentrations below the MIC for several organisms, but adjustment to 2 g dosing reduced surgical site infection rates from 16.5% to 5.6%, p<0.03 (42). Mediastinitis following cardiac surgery in obese patients may also be related to inadequate antimicrobial dosing (43). Cephalo- sporin clearance may be increased in obesity, requiring repeated dosing during an operation that lasts longer than 2–3 h (44).

Despite high protein binding and distribution predominantly within the extra- cellular compartment, the pharmacokinetics of ertapenem differ based on BMI (45). Following a standard 1 g intravenous dose, Vd was significantly higher in normal weight subjects than in obese and severely obese subjects (0.078 L/kg vs 0.063 L/kg and 0.057 L/kg) (45). The significantly lower drug exposure (i.e., AUC_0–1) in the obese and severely obese subjects translates into lower probability of attaining drug exposure targets at a given MIC compared with normal weight subjects (45). Further data are still needed to recommend more optimal drug- dosing schemes for patients with poor nutritional status.

(32)

4.2. Food Effect on Drug Disposition 4.2.1. FOOD INGENERAL

Oral drug administration concurrent with food intake alters the physicochemical conditions within the gastrointestinal tract and may influence the rate and/or extent of drug absorption. The latter is more clinically significant varying with drug properties and meal characteristics. The ability to predict the influence of food on drug disposition has become more grounded in science (46). Prediction based on classifications of physicochemical drug properties (e.g., Biopharmaceutics Classi- fication System [BCS] (47) or the Biopharmaceutics Drug Disposition Classifica- tion System [BDDCS] (48)) together with physiologic variables has become useful.

The FDA issued a guidance for industry that expanded drug labeling to include this most basic of information on one aspect of drug–nutrient interactions (49). The recommended test meal using the concept of worst-case scenario contains about 800–1000 kcal with about 50% of calories as fat. While valuable information is provided for clinical use of the marketed medication, it is also in the interest of drug development to identify these interactions early. The BCS data generated in cell culture can often predict human disposition although classifying medication by BDDCS may allow better prediction of food effects (46,50).

The influence of food on a once-daily orally administered iron chelating agent (deferasirox) was recently evaluated (51). This agent may be considered a BCS Class II drug whose bioavailability (70%) would be predicted to increase with a meal (52). At a dose of 20 mg/kg, the administration of deferasirox was evaluated one-half hour before a high-calorie meal (1000 kcal, 50% fat), one-half hour before or with a more standard breakfast meal (450 kcal, % fat not described), and in a fasted state (51). Drug bioavailability was increased when taken with food, and more so at higher fat content of the meal. Bioavailability was greatest when administered with a standard breakfast (1580 mmolhL¹), followed by a lower exposure when administered one-half hour before either meal (1340 mmolhL¹and 1320 mmolhL¹), and it was lowest in the fasted state (1060 mmolhL¹). The food effect is likely a result of increased solubilization at a more optimal pH, fat content, and surfactant level. From a pharmacodynamic standpoint, the plasma concentrations of iron–drug complex in patients with iron overload were unaffected by food intake (51). The current recommendation is to administer deferasirox 30 min before a meal (53). The magnitude of change in bioavailability would determine how clinically significant the difference is between the fed and fasted states. A similar approach can be taken when describing influences of specific foods or nutrients on drug disposition.

4.2.2. S^PECIFICF^{OODS OR}F^OODC^OMPONENTS

Specific foods may also have a unique influence on drug disposition. In vitro and in vivo studies help to tease apart possible mechanisms of these interactions.

Di- and trivalent cation-containing dietary products including dairy foods are known to chelate with the fluoroquinolone antibiotics and reduce their bioavailability. This remains true for the newer drugs in this class (54). Cow’s milk may also reduce drug bioavailability by its xanthine oxidase content as in the

S ECOND E DITION I NTERACTIONS H ANDBOOKOF D RUG -N UTRIENT

H ANDBOOK OF D RUG -N UTRIENT I NTERACTIONS

S ECOND E DITION

N UTRITION AND H EALTH

Adrianne Bendich, PhD, FACN, S

E

H ANDBOOK OF

D RUG -N UTRIENT I NTERACTIONS

Second Edition

Edited by

J OSEPH I. B OULLATA , P harm D

Associate Professor of Pharmacology & Therapeutics, University of Pennsylvania, School of Nursing,

Philadelphia, PA, USA

and

V INCENT T. A RMENTI , MD , P h D

Professor of Surgery,

Professor of Pathology, Anatomy and Cell Biology, Thomas Jefferson University,

Philadelphia, PA, USA

Foreword by

G IL H ARDY PhD, FRSC

Professor of Pharmaceutical Nutrition,

Faculty of Medical and Health Sciences, University of Auckland,

Auckland, New Zealand

Dedication

Series Editor Introduction

Foreword

Contents

I A PPROACHING D RUG –N UTRIENT

I NTERACTIONS

1 An Introduction to Drug–Nutrient Interactions

Joseph I. Boullata

H ^{ANDBOOK OF} D ^RUG -N ^UTRIENT I NTERACTIONS

S ^ECOND E ^DITION

N UTRITION AND H ^EALTH

H ^{ANDBOOK OF}

D ^RUG -N ^UTRIENT I NTERACTIONS

J ^OSEPH I. B ^OULLATA , ^P ^harm ^D

V ^INCENT T. A ^RMENTI , ^MD , ^P ^h ^D

G ^IL H ^ARDY ^{PhD, FRSC}

I ^A ^PPROACHING ^D ^RUG ^–N ^UTRIENT