Drug-Drug Interactions: Scientific and Regulatory Perspectives: August; Murad; Anders; Coyle; Li: 9780120329441: Book: : eCampus.com

Drug?Drug Interactions is a comprehensive review of the scientific and regulatory perspectives of drug?drug interactions from the point-of-view of academia, industry, and government regulatory agencies. This book is intended for professionals in the pharmaceutical industry, health care, and governmental regulatory agencies. Topics of interest include the mechanistic understanding of drug?drug interactions, the prediction of drug?drug interaction potential of new drugs, and the avoidance of clinically significant drug?drug interaction in patients.

Key Features
* Provides useful references on the science of drug-drug interactions
* Describes in a basic and comprehensive manner drug-drug interactions from the mechanistic viewpoint
* Contains original data from academic and industrial laboratories
* Presents an overview of regulatory agency positions

Univ. of Maryland, Baltimore. Comprehensive review of the scientific and regulatory aspects of drug-drug interactions from the perspectives of academia, industry, and government agencies. For pharmaceutical industry professionals and regulatory agencies.

Contributors

xiii

Foreword

Preface

xvii

Overview: Pharmacokinetic Drug--Drug Interactions

Albert P. Li

Malle Jurima-Romet

Clinical Significance of Drug--Drug Interactions

(2)

Terfenadine Cardiotoxicity

(1)

Sorivudine--Fluoropyrimidine Lethality

(1)

Oral Contraceptive Failures

(1)

Mechanism of Pharmacokinetic Drug--Drug Interactions

(1)

Prediction of Drug--Drug Interactions

(1)

Definition of CYP Isozyme Specificity of Metabolism

(1)

Evaluation of CYP Inhibition Potential

(1)

Evaluation of CYP Induction Potential

(1)

Conclusions and Future Directions

(2)

Reference

(1)

Role of Cytochrome P450 Enzymes in Drug--Drug Interactions

F. Peter Guengerich

Introduction

(1)

Potential Consequences of Drug--Drug Interactions

(2)

Use of Information about Human P450s

(1)

Mechanisms of Drug Interactions Attributable to P450s

(5)

Induction

(1)

Inhibition

(3)

Stimulation

(1)

Examples of P450-Based Interactions

(8)

Cimetidine

(1)

P450 2D6

(2)

17α-Ethynylestradiol

(2)

Terfenadine

(1)

Grapefruit Juice

(1)

Erythromycin

(1)

Cyclosporin

(1)

Omeprazole

(1)

Other Issues

(2)

Barbiturate and Peroxisome Proliferation Inducers

(1)

In Vitro/in Vivo Comparisons

(1)

Summary and Conclusions

(11)

References

(10)

The Liver as a Target for Chemical--Chemical Interactions

John-Michael Sauer

Eric R. Stine

Lhanoo Gunawardhana

Dwayne A. Hill

I. Glenn Sipes

Chemically Induced Tissue Injury

(2)

The Liver as a Target Organ for Chemically Induced Toxicity

(2)

Chemical--Chemical Interactions in the Liver

(17)

The Interaction of Carbon Tetrachloride and 1,2-Dichlorobenzene (Toxicokinetic Antagonism)

(4)

The Interaction of Phenobarbital and 1-Nitronaphthalene (Toxicokinetic Potentiation and Antagonism)

(5)

The Interaction of 1,2-Dichlorobenzene and 1,3-Dichlorobenzene (Toxicokinetic or Toxicodynamic Potentiation)

(3)

The Interaction of All-trans-Retinol and Bromotrichloromethane (Toxicodynamic Potentiation)

(4)

Conclusions

(7)

References

(5)

Application of Human Liver Microsomes in Metabolism-Based Drug--Drug Interactions: In Vitro--in Vivo Correlations and the Abbott Laboratories Experience

A. David Rodrigues

Shekman L. Wong

Introduction

(3)

The Utility of in Vitro Human Drug--Drug Interaction Studies in Drug Discovery and Development

(1)

In Vitro Drug--Drug Interaction Studies

(14)

Models

(1)

New Drug Entity as Substrate

(4)

New Drug Entity as Inhibitor

(8)

In Vitro--in Vivo Correlations

(11)

Inhibition Index

(3)

Correlations with ABT-538 (Ritonavir)

(6)

Conclusions

(9)

References

(8)

Primary Hepatocyte Cultures as an in Vitro Experimental Model for the Evaluation of Pharmacokinetic Drug--Drug Interactions

Albert P. Li

Introduction

103

(1)

The Liver as an Important Organ for Drug--Drug Interaction Evaluation

104

(1)

Isolation, Culturing, and Cryopreservation of Hepatocytes

105

(2)

Advantages of Primary Hepatocytes as an Experimental System: Intact Cell Properties

107

(3)

Physiological Levels of Enzymes and Confactors

107

(1)

Complete and Uninterrupted Xenobiotic Metabolic Pathways

108

(1)

Intact Plasma Membrane

108

(2)

Validity of Primary Hepatocytes as an Experimental System for Drug Metabolism: In Vitro--in Vivo Correlation

110

(1)

Application of Primary Human Hepatocytes in the Evaluation of Pharmacokinetic Drug--Drug Interactions

111

(13)

Evaluation of Drug--Drug Interactions via CYP450 Inhibition

112

(1)

Evaluation of Drug--Drug Interactions via CYP Induction

113

(11)

Primary Human Hepatocytes in Drug--Drug Interactions: Conclusion and Future Research Directions

124

(7)

References

127

(4)

Liver Slices as a Model in Drug Metabolism

James L. Ferrero

Klaus Brendel

Introduction

131

(7)

History

132

(2)

Preparation of Liver Slices and Incubation of Drugs

134

(4)

Characteristics of Liver Slice Metabolism: Comparison with in Vivo

138

(10)

Metabolic Profiles: Qualitative/Quantitative Aspects

138

(1)

Coupled Metabolism

138

(5)

Stereoselective Metabolism

143

(4)

Species Comparisons

147

(1)

Metabolic Drug Stability: Pharmacokinetic Comparisons

148

(3)

Prediction of Metabolic Drug--Drug Interactions

151

(13)

Single Substrate/Inhibitor Concentration Studies

152

(4)

Kinetics of Liver Slice Metabolism

156

(4)

Metabolic Switching

160

(4)

Conclusions

164

(7)

References

165

(6)

Use of cDNA-Expressed Human Cytochrome P450 Enzymes to Study Potential Drug--Drug Interactions

Charles L. Crespi

Bruce W. Penman

Summary

171

(1)

Introduction

172

(2)

Methods

174

(2)

Materials

174

(1)

Metabolite Formation

174

(1)

Inhibition Studies

175

(1)

Diclofenac 4'-Hydroxylation (CYP2C9)

175

(1)

Bufuralol 1'-Hydroxylation (CYP2D6)

175

(1)

Testosterone 6β-Hydroxylation (CYP3A4)

176

(1)

Results and Discussion

176

(9)

cDNA Expression Systems

176

(2)

Cytochrome P450 Form-Selective Metabolism

178

(4)

Cytochrome P450 Inhibition

182

(3)

Conclusions

185

(4)

References

185

(4)

Pharmacokinetics of Drug Interactions

Gregory L. Kedderis

Introduction

189

(1)

Drug Interactions Affecting Absorption

190

(3)

Changes in pH

190

(1)

Complexation and Chelation

191

(1)

Effects on Gastric Emptying

191

(1)

Effects on Intestinal Blood Flow

192

(1)

Inhibition of Active Transport

192

(1)

Drug Interactions Affecting Distribution

193

(1)

Drug Interactions Affecting Metabolism

194

(6)

Inhibition

194

(3)

Enzyme Induction

197

(1)

Dietary and Environmental Factors

198

(2)

Drug Interactions Affecting Excertion

200

(1)

Drug Interactions during Liver Disease

200

(1)

Genetic Factors in Drug Interactions

201

(1)

Beneficial Drug Interactions

201

(4)

References

202

(3)

Experimental Models for Evaluating Enzyme Induction Potential of New Drug Candidates in Animals and Humans and a Strategy for Their Use

Thomas N. Thompson

Purpose/Scope

205

(1)

Introduction

206

(1)

Rationale for Evaluating Enzyme Induction Potential during Drug Development

207

(3)

Preclinical Significance

207

(1)

Clinical Significance

208

(2)

Models Available for the Evaluation of Enzyme Induction in Animals and Humans

210

(7)

Evaluation of Toxicology Data from Multiple Dose Studies

210

(1)

Western Blot Assay for Induction Screening

210

(1)

Ex Vivo Assays for Measuring Enzyme Induction in Rat Liver

211

(2)

Human Hepatocyte Model

213

(1)

Evaluation of Enzyme Induction in Humans in Vivo

214

(2)

Other Techniques

216

(1)

A Strategy for Evaluation of Enzyme Induction Potential of Drugs in Development

217

(2)

Summary

219

(12)

References

220

(11)

Metabolic Drug--Drug Interactions: Perspective from FDA Medical and Clinical Pharmacology Reviewers

John Dikran Balian

Atiqur Rahman

Case Report

231

(1)

Assessment of in Vitro Drug Metabolism

232

(3)

Chemical Inhibition Studies

233

(1)

Correlation Studies

233

(1)

Immunochemical Inhibition Studies

234

(1)

Metabolism by cDNA-Expressed P450s

234

(1)

P450 Induction Studies

234

(1)

In Vitro--in Vivo Correlation

235

(1)

Conclusions

235

(4)

References

237

(2)

Drug Interactions: Perspectives of the Canadian Drugs Directorate

Malle Jurima-Romet

Introduction

239

(3)

Categories of Drug Interactions

240

(1)

Pharmacokinetic Drug Interactions

240

(2)

Current Regulatory Approach

242

(2)

Drug Interactions as Mentioned in Guidelines

242

(1)

Role of Postmarketing Surveillance in Monitoring Drug--Drug Interactions

243

(1)

New Initiatives

244

(1)

Adverse Drug Reaction Reporting

244

(1)

Product Reassessment

244

(1)

Impact of Information Technology

244

(1)

Trends/Concerns

245

(1)

Nonprescription Drugs

245

(1)

Herbals and Alternative Medicines

246

(1)

Biologicals

246

(1)

Regulatory Research in Drugs Directorate Laboratories: Case of Terfenadine--Drug Interactions

246

(3)

General Comments on in Vitro Studies

249

(2)

General Comments on Clinical Studies

251

(1)

Conclusion

252

(3)

References

252

(3)

Overview of Experimental Approaches for Study of Drug Metabolism and Drug--Drug Interactions

Frank J. Gonzalez

Drug Metabolism and Drug Interactions

255

(1)

Drug-Metabolizing Enzymes

256

(1)

Species Differences

257

(2)

Methods for Studying Drug Metabolism for Prediction of Drug Interactions

259

(10)

Whole Cell Systems

260

(2)

Transgenic Mice

262

(1)

In Vitro Systems

262

(3)

Recombinant P450s

265

(2)

Substrate--Activity Relationships

267

(1)

Reporter Gene Systems to Predict Inducers

268

(1)

A Case Study with Taxol Metabolism

269

(1)

Conclusions

270

(9)

References

271

(8)

Index

279

(12)

Contents of Previous Volumes

291




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