Drug Metabolism in Drug Design and Development: Basic Concepts and Practice - Hardcover

Hardcover

ISBN 10: 047173313X ISBN 13: 9780471733133

Verlag: Wiley-Interscience, 2007

Inhaltsangabe

The essentials of drug metabolism vital to developing new therapeutic entities

Information on the metabolism and disposition of candidate drugs is a critical part of all aspects of the drug discovery and development process. Drug metabolism, as practiced in the pharmaceutical industry today, is a complex, multidisciplinary field that requires knowledge of sophisticated analytical technologies and expertise in mechanistic and kinetic enzymology, organic reaction mechanism, pharmacokinetic analysis, animal physiology, basic chemical toxicology, preclinical pharmacology, and molecular biology. With chapters contributed by experts in their specific areas, this reference covers:
*

Basic concepts of drug metabolism
*

The role of drug metabolism in the pharmaceutical industry
*

Analytical techniques in drug metabolism
*

Common experimental approaches and protocols

Drug Metabolism in Drug Design and Development emphasizes practical considerations such as the data needed, the experiments and analytical methods typically employed, and the interpretation and application of data. Chapters highlight facts, common protocols, detailed experimental designs, applications, and limitations of techniques.

This is a comprehensive, hands-on reference for drug metabolism researchers as well as other professionals involved in pre-clinical drug discovery and development.

Über diesen Titel

Über die Autorin bzw. den Autor

Donglu Zhang, PhD, is a senior scientist in the Biotransformation Depart-ment at Bristol-Myers Squibb. His research interests include metabolite characterization, drug metabolism enzymology, LC/MS methodologies, and microbial biotransformation.

MINGSHE ZHU, PhD, is a drug metabolism scientist with more than ten years of experience in drug discovery and development. His research interests include metabolic activation, LC/MS technology, and regulatory drug metabolism.

W. Griffith Humphreys, PhD, is the Director of the Biotransformation Department at Bristol-Myers Squibb. His research interests include optimizationof ADME properties, metabolic activation, and new methodologies for metabolite characterization.

Von der hinteren Coverseite

The essentials of drug metabolism vital to developing new therapeutic entities

Information on the metabolism and disposition of candidate drugs is a critical part of all aspects of the drug discovery and development process. Drug metabolism, as practiced in the pharmaceutical industry today, is a complex, multidisciplinary field that requires knowledge of sophisticated analytical technologies and expertise in mechanistic and kinetic enzymology, organic reaction mechanism, pharmacokinetic analysis, animal physiology, basic chemical toxicology, preclinical pharmacology, and molecular biology. With chapters contributed by experts in their specific areas, this reference covers:

• Basic concepts of drug metabolism

• The role of drug metabolism in the pharmaceutical industry

• Analytical techniques in drug metabolism

• Common experimental approaches and protocols

Drug Metabolism in Drug Design and Development emphasizes practical considerations such as the data needed, the experiments and analytical methods typically employed, and the interpretation and application of data. Chapters highlight facts, common protocols, detailed experimental designs, applications, and limitations of techniques.

This is a comprehensive, hands-on reference for drug metabolism researchers as well as other professionals involved in pre-clinical drug discovery and development.

Aus dem Klappentext

The essentials of drug metabolism vital to developing new therapeutic entities

Information on the metabolism and disposition of candidate drugs is a critical part of all aspects of the drug discovery and development process. Drug metabolism, as practiced in the pharmaceutical industry today, is a complex, multidisciplinary field that requires knowledge of sophisticated analytical technologies and expertise in mechanistic and kinetic enzymology, organic reaction mechanism, pharmacokinetic analysis, animal physiology, basic chemical toxicology, preclinical pharmacology, and molecular biology. With chapters contributed by experts in their specific areas, this reference covers:

• Basic concepts of drug metabolism

• The role of drug metabolism in the pharmaceutical industry

• Analytical techniques in drug metabolism

• Common experimental approaches and protocols

Drug Metabolism in Drug Design and Development emphasizes practical considerations such as the data needed, the experiments and analytical methods typically employed, and the interpretation and application of data. Chapters highlight facts, common protocols, detailed experimental designs, applications, and limitations of techniques.

This is a comprehensive, hands-on reference for drug metabolism researchers as well as other professionals involved in pre-clinical drug discovery and development.

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Drug Metabolism in Drug Design and Development

John Wiley & Sons

Copyright © 2008 John Wiley & Sons, Inc.
All right reserved.
ISBN: 978-0-471-73313-3

Chapter One

OVERVIEW: DRUG METABOLISM IN THE MODERN PHARMACEUTICAL INDUSTRY

Scott J. Grossman

1.1 INTRODUCTION

It is interesting to contrast contemporary pharmaceutical biotransformation with that practiced by R.T. Williams. The fundamental objectives are virtually unchanged, to characterize the disposition of a drug in animals. In addition, then and now the routes of excretion and overall molecular transformation are still, arguably, the most important aspects of the discipline. However, in the intervening years the scope of technological advancement, scientific breadth of knowledge, and range of impact has expanded in a manner that could not have been foreseen. This chapter will give an overview of biotransformation as it is practiced in the pharmaceutical industry today.

The role of any pharmaceutical biotransformation scientist is to characterize the disposition of a drug to relate this to overall safety and efficacy. The range of information needed to characterize overall disposition is so broad that it is unlikely any single scientist will accomplish the entire characterization alone. However, it is critically important that the entire disposition process is thoroughly understood, and then intelligently integrated with other pertinent aspects of the drug's behavior. The history of contemporary pharmaceutical industry is replete with examples of how the lack of fundamental scientific knowledge (e.g., mechanism and effects of enzyme induction), appreciation of known metabolic effects (e.g., metabolic activation to toxic reactive metabolites), or incomplete integration of existing information (e.g., drug-drug interactions) led to drastically adverse outcomes. It could be argued that proper integration of information is both more difficult and important than the process of collecting the data itself. Thus, the challenge to the scientist today is to be able to comprehend decades of scientific knowledge, master an array of sophisticated technology, and integrate a diverse range of information to form a sound understanding of a drug's ultimate clinical behavior.

1.2 TECHNOLOGY

There is now an awe-inspiring array of technology available to aid the study of drug disposition. Consider that what once may have taken Williams nearly 6 months to accomplish, might only take about 20 min for a contemporary biotransformation scientist. This modern armamentarium has done much to integrate the power of biotransformation into pharmaceutical discovery and development. However, this tremendous evolution in technology presents its own set of dilemmas.

Taking full advantage of any technology requires an understanding of the technology itself. Fortunately, software and hardware engineering have greatly simplified common use of very sophisticated technologies. The LC/MS/MS instrument today is as common as the HPLC diode array UV instrument 15 years ago. This easy accessibility was greatly facilitated through robust instrument design and great software engineering.

Increasingly, the dilemma is not so much instrument access, as it is a thoughtful choice of exactly what experimental approaches and technology should be chosen to answer the question at hand. The biotransformation scientist is obliged to stay aware of technological innovations of all sorts, including instrumentation. However, the ultimate challenge should always be how to answer the most critical questions in the soundest way. True mastery of technology allows the scientific approach to follow naturally. The temptation to throw technological "sleights of hand" at a problem is often hard to resist.

Every technology has its inherent limits. Often, the specificity that enables prodigious sensitivity can also be a powerful filter of other important information. A rigorous biotransformation scientist is able to stand back and thoughtfully interrogate the strength of her own conclusions, including the technological blind spots of the approach. With thoughtful consideration, complementary technology may be applied judiciously to either flesh out a previous area of ambiguity or address the question from an entirely different perspective. In either case, scientific credibility is served well.

1.3 BREADTH OF SCIENCE

1.3.1 Chemistry

Biotransformation is fundamentally a chemical process. Likewise, the most frequently employed and valuable studies make heavy use of analytical and bioorganic chemistry. Over time, the underlying technology has become sufficiently complex that subspecialization in individual analytical techniques is common. For example, nuclear magnetic resonance spectroscopy (NMR) is invaluable for many unambiguous metabolite structural assignments. In most pharmaceutical companies, NMR specialists are employed to completely master the various facets of the technology. In many cases, these scientists will create sophisticated coupling and decoupling sequences to provide highly specific structural information. Often, their training also makes them most qualified to interpret all forms of NMR spectroscopic data. However, the "complete" biotransformation scientist will, at a minimum, know how to employ NMR spectroscopy to advance their structural understanding of a metabolite. Increasingly, the use of heteronuclear decoupling experiments is considered almost routine in the art.

Furthermore, biotransformation scientists are often fully capable of interpreting the spectra to deduce structure and are also able to recognize when such spectra still leave absolute structural assignments tentative. When one then considers the broader range of additional spectroscopic and chromatographic techniques employed in biotransformation studies, one soon recognizes the degree of technical sophistication required to be an effective biotransformation scientist.

Often, the definitive elucidation of a molecule's metabolic pathway is considered the ultimate goal of biotransformation studies. Proper application of analytical techniques, for the most part, will often be sufficient to achieve this goal. However, as often as it is "good enough" to simply define what has happened to a molecule, there are probably twice as many instances where it is also important to understand how these changes happened. The best biotransformation scientists are usually good "electron pushers." That is, their knowledge of bioorganic chemistry allows them to understand the mechanism of the molecular rearrangements taking place in each biotransformation process. They are able to both rationalize most biotransformations in a mechanistic sense and recognize when a proposed metabolite structure seems untenable. It is not uncommon to encounter a set of spectroscopic data that seems quite inconsistent with the parent molecule. In these cases, the fundamental principles of bioorganic chemistry are employed to rationalize putative structures that would be consistent with the data.

Increasingly, the roles of medicinal chemists and biotransformation scientists intersect in the discipline of bioorganic chemistry. Frequently, they share a mutual interest in decreasing metabolic liability through structural modification as well as avoiding creation of reactive metabolites through informed molecular design. Fortunately, their common understanding of bioorganic chemistry also greatly facilitates the intelligent redesign of structures to mitigate these liabilities. At its best, this requires the best of both disciplines and each scientist can develop a...

Details zur Ausgabe

• Verlag: Wiley-Interscience
• Erscheinungsdatum: 2007
• Sprache: Englisch
• ISBN 10: 047173313X
• ISBN 13: 9780471733133
• Einband: Gebundene Ausgabe
• Auflage: 1
• Anzahl der Seiten: 632
• Herausgeber: Zhang Donglu, Zhu Mingshe, Humphreys William G.
• Kontakt zum Hersteller: Wiley-VCH GmbH; product_safety@wiley.com; ; Boschstrasse 12; Weinheim; 69469; Deutschland