Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and Identification

ISBN-13: 9780470504789 / Angielski / Twarda / 2010 / 344 str.

Ala F. Nassar;¬Abar;¬Abar

Opis

The goal of this book is to improve the readers' knowledge of metabolite elucidation in drug metabolism by exposing them to in depth coverage of the biotransformation of xenobiotics, strategies for identifying and characterizing metabolites, FDA guidelines, and case studies on how to improve the decision-making process in structural modification of drug candidates to reduce toxicity. The book consists of 8 chapters; it first provides an introduction on biotransformation of xenobiotics, and then presents modern approaches and strategies for dealing with metabolite characterization, using tools such as LC-MS, H-D exchange, stable isotopes LC-MS-NMR, and radiolabeled compounds. Also, strategies for dealing with reactive intermediates in drug discovery and development are presented as well as case studies on improving the decision-making process in the structural modification of drug candidates. The last chapter discusses the regulatory perspectives of safety testing of drug metabolites and why, how, and when to test their safety.

Recenzje

"Contributors mostly from pharmaceutical companies provide a systematic introduction to characterizing metabolites, which has become an important element in drug discovery. They write for scientists involved in designing, developing, and advancing metabolic characterizations for drug discovery and development, and for researchers and students in fields that might call for such characterizations." ( Book News Inc., February 2011)

Spis treści

PREFACE.

CONTRIBUTORS.

1 HUMAN BIOTRANSFORMATION (Andrew Parkinson, Brian W. Ogilvie, Brandy L. Paris, Tiffi ni N. Hensley, and Greg J. Loewen).

2 ANALYTICAL TOOLS AND APPROACHES FOR METABOLITE IDENTIFICATION IN DRUG METABOLISM (Yongmei Li).

3 TOOLS OF CHOICE FOR ACCELERATING METABOLITE IDENTIFICATION: MASS SPECTROMETRY TECHNOLOGY DRIVES METABOLITE IDENTIFICATION STUDIES FORWARD (Ala F. Nassar).

4 IMPROVING DRUG DESIGN: CONSIDERATIONS FOR THE STRUCTURAL MODIFICATION PROCESS (Ala F. Nassar).

5 CASE STUDY: THE UNANTICIPATED LOSS OF N₂ FROM NOVEL DNA ALKYLATING AGENT LAROMUSTINE BY COLLISION–INDUCED DISSOCIATION: NOVEL REARRANGEMENTS (Ala F. Nassar, Jing Du, David Roberts, Kevin Lin, Mike Belcourt, Ivan King, and TuKiet T. Lam).

6 CASE STUDY: IDENTIFICATION OF IN VITRO METABOLITE/DECOMPOSITION PRODUCTS OF THE NOVEL DNA ALKYLATING AGENT LAROMUSTINE (Ala F. Nassar, Jing Du, David Roberts, Kevin Lin, Mike Belcourt, Ivan King, and TuKiet T. Lam).

7 STRATEGIES FOR THE DETECTION OF REACTIVE INTERMEDIATES IN DRUG DISCOVERY AND DEVELOPMENT (Mark P. Grillo).

8 SAFETY TESTING OF DRUG METABOLITES: MIST GUIDANCE IMPACT ON THE PRACTICE OF INDUSTRIAL DRUG METABOLISM (J. Greg Slatter).

INDEX.

O autorze

ALA F. NASSAR, PHD, has worked in the pharmaceutical industry for more than ten years. For over five years, Dr. Nassar oversaw the drug metabolism and bioanalytical department at Vion Pharmaceuticals, working in these key areas of drug discovery and development. One principal area of his research involved understanding how structure modification can improve the ADME profile for new chemical entities as they advance toward clinical candidacy. He identified and subsequently patented pharmacologically active metabolites of Nexavar (sorafenib), and recently identified the pharmacologically active metabolite of Onrigin (laromustine), and is in the process of seeking a patent on this discovery. Dr. Nassar has more than fifty publications in journal articles and book chapters; and has taught and coordinated several courses on bioanalytical chemistry, LC–MS, and drug metabolism to share his experience with other scientists in the field. Currently, he is the Director of the Mass Spectrometry Facility and Research Assistant Professor at Brandeis University.

Blurb

An Up–To–Date Guide on the Exciting Possibilities of Metabolite Identification in Drug Discovery

Over the years, metabolite identification and characterization have progressed to the point where they now play a major role in drug discovery and development. In particular, the metabolite elucidation of xenobiotics has been instrumental in increasing the success rate of selected drug candidates that hold the most promise for being safe and effective.

To explore the analytical possibilities present in this field, this book provides in–depth coverage on designing, developing, and advancing metabolite characterization for drug research. It discusses topics ranging from how and when to perform metabolite identification and characterization to perspectives on regulatory requirements. Biotransformation and Metabolite Elucidation of Xenobiotics also:

• Excellent primer and updated chapter on human biotransformation by Dr. Parkinson

• Supplies up–to–date details on the tools and techniques needed to perform metabolite identification

• Presents modern approaches and strategies to deal with metabolite characterization, using techniques such as LC–MS , H–D exchange, stable isotopes, and LC–MS–NMR

• Provides case studies to help improve the decision–making process in the structural modification of drug candidates?enhancing metabolic stability, improving PK properties, and reducing toxicity

• Includes FDA guidelines such as "Safety Testing of Drug Metabolites"

Giving direction and focus to improving drug discovery techniques, Biotransformation and Metabolite Elucidation of Xenobiotics is a pioneering guide rich in content that displays the verve of experts passionate about their work. It carefully and systemically approaches educating researchers and students to instill them with a better understanding on how to apply the principles of metabolite identification to create drugs that are safer, more targeted, and able to perform to the highest standards.