Presystemic Drug Elimination (eBook)

Front Cover 1
Presystemic Drug Elimination 4
Copyright Page 5
Table of Contents 10
List of Contributors 8
Preface 6
Section 1: Gastrointestinal tract 12
Chapter 1. First-pass metabolism within the lumen of the gastrointestinal tract 14
DRUG METABOLIZING OR INACTIVATING SYSTEMS OCCURRING IN THE GUT LUMEN 14
METHODS FOR STUDYING THE ROLE OF THE GUT FLORA IN FIRST-PASS METABOLISM 24
REGIONAL VARIATION IN THE EXTENT OF FIRST-PASS METABOLISM 26
EXAMPLES OF FIRST-PASS METABOLISM IN THE GUT LUMEN 27
CONCLUSION 34
References 34
Chapter 2. Metabolism of drugs by the gastrointestinal tract 40
INTRODUCTION 40
INDUCTION OF INTESTINAL DRUG METABOLISM 47
CONCLUSION 49
References 50
Chapter 3. In vivo studies of gut wall metabolism 54
INTRODUCTION 54
SIGNIFICANCE OF GUT METABOLISM: ROUTE-DEPENDENT METABOLIC PROFILES 54
METHODS OF ASSESSING GUT METABOLISM IN VIVO 56
PREABSORPTIVE VERSUS POST ABSORPTIVE GUT WALL DRUG ELIMINATION 61
IN VIVO METABOLISM OF INDIVIDUAL DRUGS 62
PHARMACOLOGICAL MODIFICATION OF GUT WALL METABOLISM 70
Induction 70
Inhibition 70
References 71
Section 2: Liver 78
Chapter 4. Presystemic drug metabolism in the liver 80
INTRODUCTION 80
DETERMINANTS OF HEPATIC DRUG METABOLISM IN VIVO 81
RANGE OF METABOLIC REAC.ONS OCCURRING WITHIN THE LIVER 82
METHODS OF DEMONSTRATING HEPAWC FIRST-PASS METABOLISM 82
RANGE OF DRUGS UNDERGOING EXTENSIVE HEPATIC PRESYSTEMIC METABOLISM 85
DOSE-DEPENDENT PRESYSTEMIC METABOLISM 85
VARIATIONS IN HEPATIC PRESYSTEMIC DRUG METABOLISM 86
CONCLUSIONS 86
References 86
Chapter 5. Physiological factors affecting hepatic first-pass metabolism 89
INTRODUCTION 89
THE VENOUS EQUILIBRATION MODEL OF HEPATIC ELIMINATION 90
INTRINSIC CLEARANCE AND FIRST-PASS METABOLISM 91
LIVER BLOOD FLOW AND FIRST-PASS METABOLISM 95
BINDING BY BLOOD CONSTITUENTS 99
FUTURE PERSPECTIVES 101
CONCLUSIONS 102
Acknowledgement 102
References 103
Chapter 6. Presystemic hepatic drug elimination in cirrhosis 107
INTRODUCTION 107
PHARMACOKINETIC APPROACHES TO EVALUATING THE HEPATIC CIRCULATION 113
CONCLUSIONS 116
References 117
Section 3: Lung 120
First-pass metabolism by the lung: introduction 122
STRUCTURE AND FUNCTION OF THE LUNGS 122
QUANTITATIVE ASPECTS OF FIRST-PASS METABOLISM BY THE LUNGS 124
References 127
Chapter 7. The metabolic potential of the lungs 128
INTRODUCTION 128
COMPOUNDS METABOLIZED BY THE LUNGS 129
OXIDATION 131
REDUCTION 134
CONJUGATION 135
HYDROLYSIS 137
FACTORS WHICH INFLUENCE THE METABOLIC POTENTIAL OF THE LUNGS 138
CONCLUSION 144
References 144
Chapter 8. First-pass metabolism of endogenous and exogenous substrates by lung 158
INTRODUCTION 158
PHARMACOKINETIC PROPERTIES OF NORMAL LUNG 158
FACTORS AFFECTING THE PHARMACOKINETIC FUNCTION OF LUNG 168
FATE OF EXOGENOUS SUBSTRATES 172
CONCLUSION 174
Acknowledgements 175
References 175
Chapter 9. Presystemic drug metabolism of exogenous compounds by the lung 184
METHODS OF STUDYING PRESYSTEMIC METABOLISM IN THE LUNG 184
ENTRY OF DRUGS VIA THE CIRCULATION 188
DRUGS REACHING THE LUNGS VIA THE AIRWAYS 188
PULMONARY METABOLISM AND TOXICITY 189
PULMONARY METABOLISM AND CARCINOGENICITY 190
CONCLUSION 192
References 193
Section 4: Epilogue 198
Chapter 10. Methods for distinguishing between the various sites of first-pass metabohsm in man 200
INTRODUCTION 200
METHODS OF STUDYING FIRST-PASS METABOLISM ACROSS THE GUT WALL 200
METHODS OF IDENTIFYING THE LIVER AS THE PRIME SITE OF FIRST-PASS METABOLISM 204
METHODS FOR STUDYING FIRST-PASS METABOLISM ACROSS THE LUNG 207
OTHER DRUGS 210
CONCLUSIONS 212
References 212
Index 218