Handbook of Drug-Nutrient Interactions (eBook)

Dedication 6
Acknowledgement 7
Series Editor Introduction 8
Foreword 14
Preface 17
Contents 18
Contributors 21
Part 1: Approaching Drug-Nutrient Interactions 24
An Introduction to Drug-Nutrient Interactions 25
1 Scope Of The Issue 25
2 Definitions 26
3 Perspectives 27
3.1 Historic 27
3.2 Clinician 27
3.3 Scientist 27
3.4 Regulatory 28
4 Classification And Descriptions 28
4.1 Nutritional Status Influences Drug Disposition 30
4.2 Food Effect on Drug Disposition 31
4.2.1 Food in General 31
4.2.2 Specific Foods or Food Components 31
4.2.3 Others 32
4.3 Effect of Specific Nutrients or Other Dietary Supplement Ingredients on Drug Disposition 32
4.4 Influence of Drugs on Global Nutritional Status 34
4.4.1 Food Intake and Absorption 34
4.4.2 Metabolism 34
4.5 Influence of Medication on the Status of Specific Nutrients 34
5 Moving Forward 36
5.1 Product Development and Evaluation 36
5.2 Patient Care 37
5.2.1 Approach 37
5.2.2 Institutional Level 37
5.2.3 Individual Practitioner-Patient Level 38
6 Final Thoughts 42
References 42
Drug Disposition and Response 49
1 Introduction 49
2 Pharmacokinetics 49
2.1 Absorption 50
2.1.1 Systemic Routes 50
2.1.2 Topical Routes 51
2.1.3 Other Routes 51
2.1.4 Factors that Affect Absorption 51
2.2 Distribution 51
2.2.1 Plasma Protein Binding 51
2.2.2 First-Pass Effect 52
2.2.3 Blood-Brain Barrier 53
2.2.4 Biological Membranes 53
2.2.5 Bioavailability 54
2.2.6 Factors that Affect Distribution 55
2.3 Metabolism 55
2.3.1 Phase 1 Reactions 55
2.3.1.1. Oxidation 55
2.3.1.2. Reduction 56
2.3.1.3. Hydrolysis 56
2.3.2 Phase 2 Reactions 56
2.3.3 Sequence of Metabolism 56
2.3.4 Induction or Inhibition 56
2.3.5 Factors that Affect Metabolism 57
2.4 Elimination 57
2.4.1 Routes of Elimination 57
2.4.2 Rate of Elimination 57
2.4.3 Clearance 58
2.4.4 Effect of Multiple Dosing 58
2.4.5 Factors that Affect Elimination 58
2.5 Pharmacogenetics 58
3 Pharmacodynamics 59
3.1 Mechanisms of Action 59
3.1.1 Antibiotics/Antivirals 59
3.1.2 Cancer Chemotherapy 59
3.1.3 Antacids 60
3.1.4 Modulation 60
3.2 Receptors 60
3.2.1 Occupation Theory 60
3.2.2 Agonists and Antagonists 60
3.2.3 Signal Fidelity 61
3.2.4 ‘‘Up-’’ and ‘‘Downregulation’’ 61
3.3 Signal Transduction 61
3.3.1 Ligand-Gated Ion Channels 61
3.3.2 GPCRs 61
3.3.3 Tyrosine Kinase Receptors 62
3.3.4 Nuclear Receptors 62
3.4 Dose-Response Curves 62
3.4.1 Quantal 62
3.4.2 Graded 62
3.4.3 Log 62
3.4.4 Potency and Efficacy 62
3.4.5 Antagonism 63
4 Conclusion 64
References 64
Drug Transporters 66
1 Introduction 66
2 Transporters And Drug Disposition 67
3 Uptake Transporters 67
3.1 Organic Anion Transporting Polypeptides 67
3.1.1 Oatp1a2 (Oatp-A Slco1a2)
3.1.2 Oatp2b1 (Oatp-B Slco2b1)
3.1.3 Oatp1b1 (Oatp-C Slco1b1)
3.1.4 Oatp1b3 (Oatp8 Slco1b3)
3.1.5 Other OATPs 72
3.2 Major Facilitator Superfamily (SLC22) 73
3.2.1 Organic Cation Transporter 1 (OCT1 SLC22A1)
3.2.2 Organic Cation Transporter 2 (OCT2 SLC22A2)
3.2.3 Organic Cation Transporter 3 (OCT3 SLC22A3)
3.2.4 Organic Anion Transporter 1 (OAT1 SLC22A6)
3.2.5 Organic Anion Transporter 2 (OAT2 SLC22A7)
3.2.6 Organic Anion Transporter 3 (OAT3 SLC22A8)
3.2.7 Organic Anion Transporter 4 (OAT4 SLC22A9)
4 Efflux Transporters 75
4.1 ATP-Binding Cassette Transporter Superfamily 75
4.1.1 Multidrug Resistance Protein 1 (MDR1, P-gp ABCB1)
4.1.2 Breast Cancer Resistance Protein (BCRP ABCG2)
4.1.3 Bile Salt Export Pump (BSEP ABCB11)
4.1.4 Multidrug Resistance-Associated Protein 1 (MRP1 ABCC1)
4.1.5 Multidrug Resistance-Associated Protein 2 (MRP2 ABCC2)
4.1.6 Multidrug Resistance-Associated Protein 3 (MRP3 ABCC3)
4.1.7 Multidrug Resistance-Associated Protein 4 (MRP4 ABCC4)
4.1.8 Multidrug Resistance-Associated Protein 5 (MRP5 ABCC5)
5 Transporters And Tissue Distribution 80
5.1 Small Intestine 80
5.2 Liver 80
5.3 Kidney 80
5.4 Brain 81
6 Transporters And Genetic Heterogeneity 81
6.1 Genetic Polymorphisms in MDR1 (ABCB1) 81
6.2 Genetic Polymorphisms in OATP1B1 (SLCO1B1) 84
7 transporters and drug-drug/drug-nutrient interactions 84
7.1 MDR1 and Drug Interactions 87
7.2 OATs and Drug Interactions 87
7.3 OATPs and Fruit Juice-Drug Interactions 88
8 Transporter-Related Organ Toxicity 88
8.1 Inhibition of Bile Salt Transport and Hepatotoxicity 88
8.2 Nephrotoxicity and Transporter Involvement 89
9 Conclusions And Future Perspectives 89
References 90
Drug-Metabolizing Enzymes 106
1 Introduction 106
2 Cytochrome P450 107
2.1 CYP3A4 107
2.2 CYP2D6 108
2.3 CYP2C9 110
2.4 CYP2C19 112
2.5 CYP2B6 114
2.6 CYP2E1 115
2.7 CYP1A2 116
3 Uridine Diphosphate Glucuronosyltransferases 117
3.1 UGT2B7 118
4 Glutathione s-Transferases 118
5 Conclusion 119
References 119
Nutrient Disposition and Response 139
1 Introduction 139
2 Control Of Food Intake 139
3 Digestion And Absorption 140
3.1 Overview 140
3.2 Mouth and Esophagus 141
3.3 Stomach 141
3.4 Small Intestine 144
3.5 Large Intestine 145
3.6 Regulation 145
3.7 Absorption 145
4 Macronutrients 145
4.1 Carbohydrates 145
4.2 Proteins 146
4.3 Lipids 147
4.4 Water Absorption 148
5 Micronutrients 148
5.1 Vitamins 148
5.2 Minerals 149
6 Factors Influencing Nutrient Absorption 152
6.1 Aging 152
6.2 Disease 152
7 Conclusion 153
References 153
Part 2: Influence of Nutrition Status on Drug Disposition and Effect 154
Influence of Protein-Calorie Malnutrition on Medication 155
1 Introduction To Malnutrition 155
1.1 Malnutrition in Children 156
1.1.1 Underweight in Children 156
1.1.1.1 Definitions 156
1.1.1.2 Prevalence 156
1.1.2 Overweight in Children 157
1.1.2.1 Definition 157
1.1.2.2 Prevalence 157
1.2 Malnutrition in Adults 157
1.2.1 Underweight 157
1.2.2 Overweight 158
1.3 Secondary Malnutrition 158
1.4 Monitoring or Screening for Malnutrition 158
1.4.1 Primary Malnutrition 158
1.4.2 Secondary Malnutrition 159
2 Review Of Basic Science 160
2.1 Physiologic Changes with PCM 160
2.2 Impact on Medication 161
2.2.1 Absorption 161
2.2.2 Distribution 161
2.2.3 Metabolism 161
2.2.4 Excretion 163
2.2.5 Drug Effects 163
3 Data From Animal Experiments 163
3.1 Analgesics 163
3.2 Anesthetics 164
3.3 Antiepileptics 164
3.4 Antimicrobial Medication 164
3.4.1 Aminoglycosides 164
3.4.2 Chloramphenicol 165
3.4.3 Clarithromycin 165
3.4.4 Itraconazole 165
3.4.5 Oxazolidinones 166
3.4.6 Sulfadiazene 166
3.4.7 Anti-tuberculars 166
3.5 Cardiovascular Agents 167
3.6 Chemotherapeutic Agents 168
3.7 Gastrointestinal Agents 169
4 Clinical Evidence By Medication 169
4.1 Analgesics 170
4.2 Antimicrobial Medication 170
4.2.1 Aminoglycosides 170
4.2.2 Chloramphenicol 171
4.2.3 Broad-Spectrum Antibiotics 172
4.2.4 Penicillin 173
4.2.5 Anti-malarials 173
4.2.6 Anti-tuberculars 174
4.2.7 Sulfadiazine 175
4.2.8 Tetracycline 175
4.3 Anti-gout 175
4.4 Chemotherapeutic Agents 176
4.5 Gastrointestinal Agents 176
4.6 Immunosuppressants 176
5 Limitations Of Current Data 177
6 Future Research Needs 177
7 Clinical Recommendations 178
References 179
Influence of Overweight and Obesity on Medication 184
1 Introduction 184
1.1 Definitions and Prevalence of Obesity 184
1.2 Assessing Body Weight for Drug Dosing 186
2 Basic Science 190
2.1 Absorption 191
2.2 Distribution 191
2.2.1 Body Composition 191
2.2.2 Blood Flow 192
2.2.3 Protein Binding 192
2.2.4 Summing up Distribution 193
2.3 Elimination 194
2.3.1 Hepatic 194
2.3.2 Renal 195
2.4 Drug Effect 195
2.5 Integrating the Data for a Clinical Approach to the Obese Patient 196
3 Clinical Evidence 197
3.1 Antiepileptic Drugs 197
3.2 Antimicrobials 197
3.2.1 Beta-Lactams 198
3.2.2 Aminoglycosides 198
3.2.3 Glycopeptides 199
3.2.4 Fluroquinolones 199
3.2.5 Antifungals 200
3.2.6 Antivirals 200
3.2.7 Others 200
3.3 Chemotherapy 201
3.3.1 Body Surface Area, Body Weight, and Systemic Exposure 201
3.3.2 Specific Drugs 202
3.4 Immunosuppressants 202
3.5 Neuromuscular Blockers 202
3.6 Benzodiazepines 203
3.7 Anesthetics 204
3.8 Analgesics 204
3.9 Others 205
3.10 Obesity Treatments 206
3.10.1 Medications 206
3.10.2 Surgical Intervention 207
3.10.3 Other Interventions 208
4 Limitations Of The Data And Future Research 208
5 Conclusion And Recommendations 209
References 211
Part 3: Influence of Food, Nutrients, or Supplementation on Drug Disposition and Effect 223
Drug Absorption with Food 224
1 Introduction 224
2 Review Of Basic Science 228
2.1 Drug Absorption 228
2.1.1 Dependence on Drug Properties 228
2.1.2 Dependence on Dosage Form Properties 232
2.2 Meal Effects 232
2.2.1 Administered Volume 232
2.2.2 Caloric Load 233
2.2.3 Meal Type 234
2.3 Physical-Chemical Interactions in the Gastrointestinal Tract 234
2.3.1 Meal Viscosity 234
2.3.2 Meal Effects on Gastrointestinal pH 235
2.3.3 Meal Calcium Content 235
2.3.4 Drug Binding to Meal and Biliary Components 236
2.3.5 Meal Effects on First-Pass Elimination 236
2.3.5.1 First-Pass Metabolism 236
2.3.5.2 Permeability Limitations Due to Intestinal Efflux 237
2.3.6 Meal Effects and Region-Dependent Absorption 238
2.3.7 Meal Effects on Splanchnic Blood Flow 238
3 Clinical Evidence - The Case Of The Protease Inhibitors 238
4 Practical Issues And Regulatory Considerations 240
4.1 Drug Classification and Food Effects 241
4.1.1 Bioavailability 241
4.1.2 Bioequivalence 242
4.2 Food Effects on Modified-Release Formulations 242
4.2.1 Bioavailability 242
4.2.2 Bioequivalence 244
4.3 Regulatory Studies Under Fed Conditions 244
4.4 The Food-Effect Bioavailability and Fed Bioequivalence Studies Guidance 244
4.4.1 Recommendations for Immediate-Release Drug Products 245
4.4.2 Recommendations for Modified-Release Drug Products 245
4.4.3 Overview of the Guidance 246
4.4.3.1 General Design 246
4.4.3.2 Subject Selection 246
4.4.3.3 Dosage Strength 246
4.4.3.4 Test Meal 246
4.4.3.5 Administration 247
4.4.3.6 Sample Collection 247
4.4.3.7 Data Analysis 247
5 Drug Product Labeling On Food Effects 248
5.1 Labeling Examples from Approved Products 249
6 Future Research 251
7 Concluding Remarks And Recommendations 251
References 251
Effects of Specific Foods and Dietary Components on Drug Metabolism 257
1 Introduction 257
2 Studies In Healthy Subjects And Observations In Patients 257
3 Drug Metabolic Pathways Likely To Be Affected By Diet 258
4 Studies In Animals And Humans 259
4.1 Effects of Dietary Protein, Carbohydrate, and Fat 259
4.2 Cruciferous Vegetables 264
4.3 Grapefruit Juice 265
4.4 Herbs 266
4.5 Methylxanthines 267
4.6 Food Preparation 267
4.7 Tyramine and Related Substances 268
4.8 Alcohol 270
4.9 Vitamins 271
5 Conclusions And Implications 272
References 272
Grapefruit and Other Fruit Juices Interactions with Medicines 280
1 Introduction 280
2 Review of Basic Science 281
2.1 Drug Metabolism and Grapefruit Juice Effect 281
3 Clinical Evidence 284
3.1 Drug Interactions with Grapefruit Juice 284
3.2 Adverse Drug Effects with Grapefruit Juice 284
3.2.1 Torsades de Pointes 284
3.2.2 Rhabdomyolysis 288
3.2.3 Symptomatic Hypotension 289
3.2.4 Dysrhythmia 290
3.2.5 Loss of Drug Efficacy 291
3.3 Potentially Beneficial Drug Effects with Grapefruit Juice 291
3.3.1 Drug Cost Savings 291
3.3.2 Maintenance of Drug Effectiveness 292
3.3.3 Enhanced Drug Efficacy 292
3.4 Drug Interactions with Other Fruit Juices 292
3.4.1 Seville Orange Juice 293
3.4.2 Pummelo or Pomelo Juice 293
3.4.3 Lime Juice 293
3.4.4 Pomegranate Juice 294
3.4.5 Tangerine Juice 294
3.4.6 Cranberry Juice 294
3.4.7 Others 294
4 Limitations of the Data 295
4.1 Incomplete List of Drugs Interacting with Grapefruit Juice 295
4.2 Adverse Effects with Grapefruit Juice 295
5 Future Research Needs 297
5.1 Other Enzymes and Fruit Juices 297
5.1.1 CYP1A2 297
5.1.2 CYP2C9 298
5.1.3 CYP2D6 298
5.1.4 Esterases 298
5.1.5 UGT1A1 298
5.2 Drug Transporters and Fruit Juices 298
5.2.1 P-glycoprotein 299
5.2.2 Organic Anion Transporting Polypeptides (OATPs) 299
5.2.3 Other Fruit Juices 301
5.2.3.1 Orange Juice 301
5.2.3.2 Apple Juice 302
6 Clinical Recommendations 303
References 305
Positive Drug-Nutrient Interactions 316
1 Introduction 316
2 Effects Of Food On Drug Absorption 319
2.1 Anthelmintics 319
2.1.1 Albendazole 319
2.1.2 Mebendazole 319
2.2 Antibiotics 320
2.2.1 Cefuroxime 320
2.2.2 Nitrofurantoin 321
2.3 Antifungals 322
2.3.1 Griseofulvin 322
2.3.2 Itraconazole 323
2.3.3 Posaconazole 324
2.4 Antiprotozoals 325
2.4.1 Atovaquone 325
2.4.2 Nitazoxanide 326
2.5 Antiretrovirals 327
2.5.1 Atazanavir 327
2.5.2 Darunavir 327
2.5.3 Lopinavir 328
2.5.4 Nelfinavir 328
2.5.5 Saquinavir 329
2.6 Fenofibrate 330
2.7 Isotretinoin 331
2.8 Mesalamine/Olsalazine 332
2.9 Misoprostol 332
3 Effects Of Specific Nutrients On Drug Absorption 333
3.1 Ascorbic Acid and Iron 333
4 Effects Of Specific Nutrients On Reducing Drug Toxicity 335
4.1 Folic Acid and Fluorouracil 335
4.2 Folic Acid and Methotrexate 337
4.3 Pyridoxine and Isoniazid 339
5 Effects Of Specific Nutrients On Enhancing Drug Effect 340
5.1 Calcitriol and Docetaxel 340
5.2 Plant Stanols and Statins 341
6 Conclusions 345
6.1 Limitations of Current Data 345
6.2 Research Needs 345
6.3 Clinical Recommendations 345
References 346
Interaction of Natural Products with Medication and Nutrients 353
1 Background 353
1.1 Definition of Dietary Supplements 354
1.2 Prevalence of Dietary Supplement Use 355
2 Scientific Principles 358
2.1 Confounding Issues with Dietary Supplements 358
2.2 Observed and Reported Mechanism of Interactions 359
2.3 Quality of Data Available 359
3 Established Evidence 360
3.1 Garlic 361
3.2 Valerian 362
3.3 Kava 363
3.4 Ginkgo 363
3.5 St. John’s Wort 364
3.6 Glucosamine/Chrondoitin 366
3.7 Ginseng 367
3.8 Other Emerging Drug Interactions with Dietary Supplements 368
4 Summary 369
References 371
Drug-Nutrient Interactions in Patients Receiving Enteral Nutrition 379
1 Introduction 379
2 Review Of Enteral Nutrition Basics 380
2.1 Tube Placement 380
2.2 Site of Feeding 381
2.3 Administration Regimens for Enteral Feeding 382
2.4 Safety 382
3 Classes Of Interactions 383
3.1 Administration-Related Factors 385
3.1.1 Tube Characteristics 385
3.1.2 Administration Regimen 385
3.1.3 The Site of Feeding 389
3.2 Drug-Related Factors 390
3.2.1 Dosage Forms 390
3.2.2 The Absorptive Environment 400
3.2.2.1 Stomach 401
3.2.2.2 Small Bowel 401
3.2.2.3 Gastric Administration 403
3.2.2.4 Post-pyloric Administration 404
3.2.3 Therapeutic Index 406
3.3 Formula-Related Factors 406
3.3.1 Protein Content 406
3.3.2 Components Influencing GI Motility 408
3.3.3 Vitamin K Content 409
3.4 Disease-Related Factors 411
3.4.1 Visceral Protein Status 411
3.4.2 GI Motility 412
4 Specific Drugs 412
4.1 Phenytoin 412
4.2 Carbamazepine 414
4.3 Fluoroquinolones 415
4.4 Warfarin 416
4.5 Theophylline 416
4.6 Levothyroxin 417
4.7 Penicillin V Potassium 417
5 Conclusion 417
References 418
Drug-Nutrient Interactions in Patients Receiving Parenteral Nutrition 423
1 Introduction 423
2 Parenteral Nutrition 423
2.1 Definitions 423
2.2 Indications for PN 424
3 Compatibility And Stability Of Drugs With Pn 425
3.1 General 425
3.2 Admixture Compatibility and Stability 428
3.3 Co-infusion Compatibility and Stability 429
4 Influence Of Pn On Pharmacodynamics And Pharmacokinetics Of Drugs 432
4.1 Glycemic Control 432
4.2 Oral Anticoagulants 433
4.3 Influence of PN on Drug Elimination 433
4.4 Others 434
5 SUMMARY 434
References 435
Part 4: Influence of Medication on Nutrition Status, Nutrient Disposition, and Effect 437
Drug-Induced Changes to Nutritional Status 438
1 Introduction 438
2 Drugs associated with weight gain 438
2.1 Psychotropic Agents 439
2.2 Antidiabetic Agents 439
2.3 Steroids 439
2.4 Management 439
3 Drugs associated with weight loss 440
3.1 Stimulants 440
3.2 Others 440
3.3 Drugs with Potentially Excessive Social Use 441
3.4 Management 441
4 Altered Taste Perception 441
4.1 Drug Induced 441
4.2 Management 445
5 Drugs Altering Gastrointestinal Function 446
5.1 Overview of Gastrointestinal Function 446
5.2 Drug-Induced Emesis 446
5.3 Drug-Induced Motility Disturbances 447
5.3.1 Increased Motility 447
5.3.2 Decreased Motility 447
6 Drug-Induced Metabolic Effects 448
6.1 Hyperglycemia 448
6.2 Hypoglycemia 448
6.3 Lipid Changes 449
6.4 Protein Effects 449
7 Drug-Induced Nutrient Depletions 449
8 Summary 453
References 454
Influence of Cardiovascular Medication on Nutritional Status 457
1 Introduction 457
2 Antiadrenergic agents 458
2.1 beta-Blockers and alpha/beta-Adrenergic Blocking Agents 458
2.1.1 General 458
2.1.1.1 Influence of Obesity 458
2.1.1.2 Influence on Nutritional Parameters 459
2.1.2 Acebutolol 459
2.1.3 Atenolol 460
2.1.4 Carvedilol 460
2.1.5 Propranolol 460
2.1.6 Others 460
2.2 Centrally Acting Antiadrenergics 460
2.2.1 General 460
2.2.2 Clonidine 460
2.3 Peripherally Acting Antiadrenergics 461
2.3.1 General 461
2.3.2 Doxazosin 461
2.3.3 Terazosin 461
3 Antiarrhythmic Medications 461
3.1 General 461
3.2 Amiodarone 461
3.3 Disopyramide 462
3.4 Flecainide 462
3.5 Lidocaine 462
3.6 Procainamide 462
3.7 Propafenone 462
3.8 Quinidine 462
3.9 Sotalol 463
4 Antithrombotic agents 463
4.1 Aspirin 463
4.2 Cilostazole 465
4.3 Clopidogrel 465
4.4 Dipyridamole 465
4.5 Fondaparinux 466
4.6 Heparin 466
4.6.1 Effect of Heparin on Nutrition Status 466
4.6.2 Influence of Nutrition on Heparin 466
4.7 Warfarin 466
5 Calcium channel blockers 468
5.1 General 468
5.2 Amlodipine 469
5.3 Felodipine 469
5.4 Isradipine 469
5.5 Nifedipine 469
5.6 Verapamil 470
5.7 Manidipine 470
6 Cardiac Glycosides 470
7 Diuretics 471
7.1 Diazoxide 471
7.2 Loop Diuretics 471
7.3 Potassium-Sparing Diuretics 472
7.4 Thiazide/Thiazide-Like Diuretics 472
8 Renin-Angiotensin-Aldosterone System (Raas) Agents 473
8.1 Angiotensin-Converting Enzyme Inhibitors 473
8.1.1 General 473
8.1.2 Specific Agents 474
8.2 Angiotensin Receptor Blockers 475
8.2.1 General 475
8.2.2 Specific Agents 475
8.3 Others 475
8.3.1 Aldosterone Blockers 475
8.3.2 Renin Inhibitors 475
9 Lipid Modulating Agents 476
9.1 HMG-CoA Reductase Inhibitors 476
9.1.1 General 476
9.1.2 Atorvastatin 476
9.1.3 Rosuvastatin 476
9.1.4 Simvastatin 476
9.1.5 Lovastatin 476
9.1.6 Fluvastatin 476
9.1.7 Pravastatin 477
9.2 Niacin 477
9.3 Fibric Acids 477
9.3.1 General 477
9.3.2 Fenofibrate 477
9.3.3 Gemfibrozil 478
9.4 Bile Acid Resins 478
9.4.1 Cholestyramine, Colestipol, and Colesevelam 478
9.5 Cholesterol Absorption Inhibitors 478
9.5.1 Ezetimibe 478
9.6 Omega-3 Fatty Acids 478
10 Organic nitrates 479
10.1 Isosorbide Mononitrate 479
11 Vasoactive Agents 479
11.1 Dobutamine, Amrinone, and Norepinphrine 479
11.2 Epinephrine 480
11.3 Bosentan 481
11.4 Hydralazine 481
12 Clinical relevance 481
13 Limitations of the Data 481
14 Research needs 482
15 Clinical Recommendations 482
References 482
Influence of Neurological Medication on Nutritional Status 493
1 Introduction 493
2 Antiepileptic Drugs 493
2.1 Bone Mineral Status 494
2.1.1 Review of Mechanisms/Scientific Basis 494
2.1.2 Reported Cases/Descriptions 495
2.1.3 Clinical Relevance 496
2.1.4 Limitations of Data 497
2.1.5 Research Needs 497
2.1.6 Clinical Recommendations 497
2.2 B-Vitamin Status 499
2.2.1 Review of Mechanisms/Scientific Basis 499
2.2.2 Reported Cases/Descriptions 501
2.2.3 Clinical Relevance 503
2.2.4 Limitations of Data 504
2.2.5 Research Needs 504
2.2.6 Clinical Recommendations 504
2.3 Hyperammonemia 505
2.3.1 Review of Mechanisms/Scientific Basis 505
2.3.2 Reported Cases/Descriptions 506
2.3.3 Clinical Relevance 506
2.3.4 Limitations of Data 506
2.3.5 Research Needs 506
2.3.6 Clinical Recommendations 507
2.4 Enteral Nutrition and Antiepileptic Drugs 507
2.4.1 Review of Mechanisms/Scientific Basis 507
2.4.2 Reported Cases/Descriptions 507
2.4.3 Clinical Relevance 508
2.4.4 Limitations of Data 508
2.4.5 Research Needs 508
2.4.6 Clinical Recommendations 508
3 Dopaminergic Drugs/Anti-Parkinsonian Agents 508
3.1 Levodopa 508
3.1.1 Review of Mechanisms/Scientific Basis 508
3.1.2 Reported Cases/Descriptions 509
3.1.3 Clinical Relevance 510
3.1.4 Limitations of Data 510
3.1.5 Research Needs 510
3.1.6 Clinical Recommendations 510
3.2 Other Dopamine Agonists 510
4 Cerebrovascular accident 511
4.1 Warfarin 511
4.1.1 Review of Mechanisms/Scientific Basis 511
4.1.2 Reported Cases/Descriptions 511
4.1.3 Clinical Relevance 512
4.1.4 Limitations of Data 512
4.1.5 Research Needs 512
4.1.6 Clinical Recommendations 513
5 Management Of Traumatic Brain Injury 513
5.1 Mannitol 513
5.1.1 Review of Mechanisms/Scientific Basis 513
5.1.2 Reported Cases/Descriptions 513
5.1.3 Research Needs 514
5.1.4 Clinical Recommendations 514
5.2 Propofol 514
5.2.1 Review of Mechanisms/Scientific Basis 514
5.2.2 Reported Cases/Descriptions 514
5.2.3 Clinical Relevance 515
5.2.4 Research Needs 515
5.2.5 Clinical Recommendations 515
5.3 Hypertonic Saline Therapy 515
5.3.1 Review of Mechanisms/Scientific Basis 515
5.3.2 Clinical Relevance 515
5.3.3 Limitations of Data 515
5.3.4 Research Needs 516
5.3.5 Clinical Recommendations 516
6 Summary 516
References 516
Drug-Nutrient Interactions Involving Folate 522
1 Introduction 522
2 Basic Review Of Folate 522
2.1 Description 522
2.2 Folate Deficiency 523
2.2.1 Risk Factors 523
2.2.2 Identifying Folate Deficiency 524
2.3 Folate Requirements 525
2.4 Safety of Folic Acid Supplementation 526
2.5 Folate Disposition 527
2.5.1 Overview 527
2.5.2 Polymorphisms of Enzymes Involved in Folate Metabolism 528
3 Drug-Folate Interactions 528
4 Limitations Of The Data And Further Research Needs 529
5 Recommendations 530
6 Summary 540
References 541
Drug-Nutrient Interactions That Impact on Mineral Status 546
1 Introduction 546
2 Overview of mineral absorption and bioavailability 547
3 Macrominerals 548
3.1 Sodium 549
3.1.1 Drug Interactions 549
3.2 Potassium 552
3.2.1 Drug Interactions 552
3.3 Calcium 553
3.3.1 Drug Interactions 553
3.4 Phosphorus 554
3.4.1 Drug Interactions 554
3.5 Magnesium 556
3.5.1 Drug Interactions 556
4 Trace and Ultratrace Minerals 561
4.1 Iron 561
4.1.1 Drug Interactions 561
4.2 Copper 562
4.2.1 Drug Interactions 563
4.3 Zinc 563
4.3.1 Drug Interactions 564
4.4 Chromium 565
4.4.1 Drug Interactions 565
4.5 Selenium 566
4.5.1 Drug Interactions 566
4.6 Fluoride 566
4.6.1 Drug Interactions 567
4.7 Iodine 567
4.7.1 Drug Interactions 568
4.8 Other Minerals 568
5 Other Substances Affecting Mineral Status 569
5.1 Ethanol 569
5.2 Caffeine 569
5.3 Smoking 569
5.4 Illicit Substances 570
6 Limitations Of Current Data And Future Research Needs 571
7 Clinical Recommendations 571
References 573
Part 5: Drug-Nutrient Interactions by Life Stage 581
Drug-Nutrient Interactions in Infancy and Childhood 582
1 Introduction 582
2 Growth And Development 584
3 Nutritional Assessment 585
4 Nutritional Requirements 588
5 Medication Administration And Drug Absorption 589
5.1 pH Effects 590
5.2 Phenytoin and Enteral Feeds 591
5.3 Ciprofloxacin and Enteral Feeds 591
5.4 Effect of Food on Drug Absorption 591
5.4.1 Contradictory and Additive Effects 592
6 Natural Health Products 592
7 Management Of Drug-Nutrient Interactions 593
7.1 Identification 593
7.2 Prevention 595
7.3 Management 595
8 Future Directions 596
References 596
Drug-Nutrient Interaction Considerations in Pregnancy and Lactation 599
1 Introduction 599
2 Maternal physiological changes in pregnancy: their impact on drug pharmacokinetics and disposition 600
2.1 Drug Absorption 600
2.2 Distribution 601
2.3 Placental Transfer 601
2.4 Protein Binding 602
2.5 Metabolism 602
2.6 Elimination 602
2.7 Adherence 602
2.8 Clinical Relevance 602
3 Nutrient Requirements in Pregnancy 603
3.1 Folic Acid 603
3.2 Iron 607
3.3 Vitamin A 607
4 Special maternal considerations: drugs and disease which affect nutrient status 608
4.1 Antiepileptics and Vitamin K 608
4.2 Folic Acid Antagonists 608
4.3 Hyperemesis Gravidarum 609
5 Physiologic Changes and Nutrient Requirements in Lactation 609
6 Drug Distribution into Human Milk 610
6.1 Expressing and Quantifying Infant Exposure 611
6.2 Infant Issues 613
7 Special considerations: drugs that influence milk production or infant intake 613
7.1 Drugs that Increase Milk Production 613
7.2 Drugs that May Decrease Milk Yield 616
8 Summary And Recommendations 616
References 617
Drug-Nutrient Interactions in the Elderly 623
1 Introduction 623
1.1 The Elderly 623
1.2 Medication Use 624
1.3 Appropriateness of Medication Use 625
2 A Description Of Physiologic Alterations In The Elderly 626
2.1 Body Composition 628
2.2 Gastrointestinal Function 629
2.3 Liver Function 630
2.4 Renal Function 631
2.5 Pharmacokinetics and Pharmacodynamics 631
2.6 Nutritional Status 634
3 Clinical Evidence 638
3.1 Overview of Drug-Nutrient Interactions in the Elderly 638
3.2 The Effect of Food on Drug Disposition in the Elderly 639
3.2.1 Enteral Formulas 639
3.2.2 Dietary Supplements 639
3.2.3 Substances in the Diet Used Habitually 640
3.2.3.1 Caffeine 640
3.2.3.2 Ethanol 641
3.2.4 Grapefruit Juice Interactions 642
3.3 The Effect of Medication on Nutritional Status in the Elderly 643
3.3.1 Anticoagulants 643
3.3.1.1 Warfarin 643
3.3.2 Antiepileptics 644
3.3.2.1 Phenytoin 644
3.3.3 Antidepressants 645
3.3.3.1 Monoamine Oxidase Inhibitors 645
3.3.4 Antimicrobials 646
3.3.4.1 Tetracyclines and Fluoroquinolones 646
3.3.5 Endocrine Agents 646
3.3.5.1 Metformin 646
3.3.5.2 Levothyroxine 648
3.3.5.3 Bisphosphonates 648
3.3.6 Gastrointestinal Agents 649
3.3.6.1 Proton Pump Inhibitors 649
3.3.6.2 Bile Acid Sequestrants 649
3.3.6.3 Laxatives 649
3.3.7 Parkinson Agents 650
3.3.7.1 Levodopa 650
3.3.8 Weight-Influencing Medication 650
3.3.8.1 Unintentional Weight Loss 650
3.3.8.2 Unintentional Weight Gain 651
3.3.9 Other Medication-Induced Micronutrient Abnormalities 652
3.3.9.1 Diuretics 652
3.3.9.2 Hyponatremia and Hypernatremia 652
3.3.9.3 Hypokalemia and Hyperkalemia 653
3.3.9.4 Other 654
4 Limitations Of The Data 654
5 Future Research Needs 655
6 Clinical Recommendations To Prevent Or Manage Interactions In The Elderly 656
References 657
Part 6: Drug-Nutrient Interactions in Specific Conditions 669
Drug-Nutrient Interactions and Immune Function 670
1 Introduction 670
2 The Human Immune System 672
2.1 Functions of Immune Organs 672
2.2 Gut Microflora and Immunity 674
2.3 Nutrients and Nutritional Status and Immunity 674
2.4 Aging of the Immune System 674
3 Overview Of Infectious Diseases And Vaccines 676
3.1 Infectious Diseases Prevalence and Evaluation of Risk Factors 686
3.1.1 Respiratory Infection 686
3.1.2 HIV Infection and AIDS 687
3.1.3 Diarrheal Diseases 688
3.1.4 Tuberculosis 688
3.2 Nutritional Status and Infectious Diseases 688
3.2.1 Vitamin A in Deficient Populations 688
3.2.2 Zinc in Deficient Populations 689
3.2.2.1 Zinc Status, Immune Function, and the Elderly 690
3.2.3 Beta-Carotene 691
3.2.4 Vitamin E 691
3.2.5 Other Relevant Essential Nutrients 692
3.2.5.1 Vitamin C 692
3.2.5.2 Vitamin D 692
3.2.5.3 Arginine and Glutamine 693
4 Effect Of Drugs (Used To Manage Major Infectious Diseases) On Nutritional Status 693
4.1 HIV 697
4.2 TB 701
5 Autoimmune Diseases 701
5.1 Autoimmune Disease Prevalence and Evaluation of Risk Factors 701
5.1.1 Rheumatoid Arthritis 702
5.1.2 Systemic Lupus Erythematosus 702
5.1.3 Inflammatory Bowel Disease 703
5.1.4 Diabetes 705
5.1.4.1 Type 1 Diabetes 705
5.1.4.2 Type 2 Diabetes 706
5.2 Nutritional Status and Autoimmune Diseases 708
5.2.1 IBD 709
5.2.2 Fiber (Prebiotics) 709
5.2.3 Probiotics 711
5.3 Nutrients as Anti-inflammatory Agents 712
5.3.1 Omega-3 Fatty Acids 712
5.3.2 RA and Other Arthritides 713
6 Effect Of Drugs (Used To Manage Autoimmune Diseases) On Nutritional Status 714
6.1 RA 714
6.2 SLE 715
6.3 Type 2 Diabetes 715
7 Conclusions 727
References 728
Drug-Nutrient Interactions in Patients with Cancer 742
1 Introduction 742
1.1 Epidemiology 742
1.2 Nutritional Status in Patients with Cancer 743
2 Evaluating Nutritional Derangements In Patients With Cancer 745
2.1 Nutritional Assessment 745
2.2 Role of Therapeutic Modalities 745
2.3 Drug-Nutrient Interaction Data 746
3 The Influence Of Nutritional Status 747
4 The Influence Of Medication 748
4.1 Gastrointestinal Function 748
4.2 Macronutrient Status 748
4.3 Fluid, Electrolyte, and Acid-Base Status 749
4.4 Vitamin Status 750
4.5 Nutrient Antioxidant Status 750
5 Other Influences 751
6 Limitations Of Current Data 751
7 Future Research 752
8 Conclusion And Recommendations 752
References 753
Drug-Nutrient Interactions in Transplantation 755
1 Introduction 755
2 Review Of Mechanisms 756
2.1 Induction Agents 756
2.1.1 Monoclonal Antibodies 756
2.1.2 Polyclonal Antibodies 757
2.2 Maintenance Agents 757
2.2.1 Corticosteroids 757
2.2.2 Calcineurin Inhibitors 758
2.2.3 mTOR Inhibitors 759
2.2.4 Antiproliferative Agents 759
3 Descriptions And Clinical Relevance Of Nutritional Status 759
3.1 Renal Transplantation 759
3.2 Liver Transplantation 760
3.3 Pancreas Transplantation 761
3.4 Heart and Lung Transplantation 762
3.4.1 Heart Transplantation 762
3.4.2 Lung Transplantation 762
3.5 Small Bowel Transplantation 763
4 Limitations Of The Data 763
5 Research Needs 764
6 Clinical Recommendations 764
References 765
Drug-Nutrient Interactions in Patients with Chronic Infections 770
1 Introduction 770
2 Mechanisms Of Drug-Nutrient Interaction 770
2.1 The Food Effect 770
2.2 Studying and Evaluating Food Effect 771
3 Drug-Nutrient Interactions For Medications Used To Treat Hiv Infection 772
3.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 773
3.1.1 Abacavir 773
3.1.2 Didanosine 773
3.1.3 Emtricitabine 773
3.1.4 Lamivudine 774
3.1.5 Stavudine 774
3.1.6 Tenofovir 774
3.1.7 Zalcitabine 774
3.1.8 Zidovudine 774
3.2 Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (Table 2) 775
3.2.1 Delavirdine 775
3.2.2 Efavirenz 776
3.2.3 Etravirine 776
3.2.4 Nevirapine 776
3.3 Protease Inhibitors (PIs) (Table 3) 777
3.3.1 Amprenavir 777
3.3.2 Atazanavir 778
3.3.3 Darunavir 778
3.3.4 Indinavir 778
3.3.5 Lopinavir/Ritonavir 779
3.3.6 Nelfinavir 779
3.3.7 Ritonavir 780
3.3.8 Saquinavir 780
3.3.9 Tipranavir 781
3.4 Newer Antiretroviral Agents (Table 4) 781
3.4.1 Maraviroc 781
3.4.2 Raltegravir 782
3.5 Alternative Therapies 782
3.6 Metabolic Impact of the Treatment of HIV Infection - Beyond the Food Effect 783
3.6.1 Fat Accumulation 783
3.6.2 Lipoatrophy 784
3.6.3 Lipid Abnormalities 784
3.6.4 Disorders of Glucose Metabolism 785
3.6.5 Hyperlactatemia and Lactic Acidosis 785
3.6.6 Bone Disorders 786
4 Drug-Nutrient Interactions For Medications Used To Treat M. Tuberculosis Infection 786
4.1 Aminosalicylic Acid Granules 787
4.2 Cycloserine 788
4.3 Ethambutol 788
4.4 Ethionamide 788
4.5 Isoniazid 788
4.6 Pyrazinamide 789
4.7 Rifabutin 789
4.8 Rifampin 789
4.9 Rifapentine 789
5 Drug-Nutrient Interactions For Medications Used To Treat Chronic Viral Hepatitis 789
5.1 Adefovir 790
5.2 Ribavirin 790
6 Conclusion 790
References 791
Index 795
About the Editors 821
About the Series Editor 823