Offering a conceptual and factual presentation of the metabolism of
drugs and other xenobiotics, these two volumes distinctly focus on
the biochemistry, with an emphasis on xenobiotic-metabolizing
enzymes, their reactions and regulations.
The first volume is divided into three parts. Part One begins by
introducing xenobiotics in the broad context of physiological
metabolism, and continues with an overview of the processes of drug
disposition and metabolism. It then goes on to summarize the
macroscopic and microscopic locations of drug metabolism in animals
and humans. This is followed by an introduction to the
all-important issue of the consequences of drug and xenobiotic
metabolism, providing an initial overview of pharmacokinetic,
pharmacological and toxicological consequences. The last chapter
examines drug metabolism in the context of drug research, with a
focus on medicinal chemistry.
The second part is a major component of the book, corresponding to
the role of oxidoreductases as major agents of metabolism.
Cytochromes P450 receive particular attention, namely their
multiplicity, structure, catalytic mechanisms, and the various
reactions they catalyze, while other oxidoreductases are also
presented, such as flavin monooxygenases, monoamine oxidases and
other amine oxidases, aldehyde oxidase and xanthine dehydrogenase,
peroxidases, and dehydrogenases-reductases. Each drug-metabolizing
enzyme or enzyme family begins with an Enzyme Identity Card
summarizing its nomenclature and biochemical essentials.
Part Three begins with a survey of the classification, properties
and catalytic mechanism of the innumerable hydrolases known or
suspected to play a role in xenobiotic metabolism. The focus then
shifts to a systematic presentation of the various substrates
classes, namely carboxylic esters, amides and peptides, lactams and
lactones, esters of inorganic acids, alkene and arene epoxides, and
some miscellaneous hydrolyzable moieties.
Volume Two contains the last four parts of this work. Part 4 is
devoted to the huge field of conjugation reactions, with much
information being given on transferases. As in the two preceding
parts, each drug-metabolizing enzyme or enzyme family begins with
an Enzyme Identity Card summarizing its nomenclature and
biochemical essentials. The reactions examined here include
methylation, sulfation, glucuronidation, acetylation, conjugation
with glutathione, while there is also a rigorous presentation of
the pivotal role of xenobiotic-coenzyme A conjugates as a
crossroads to various metabolic reactions.
The next part examines the consequences of drug and xenobiotic
metabolism in a pharmacological and toxicological perspective, with
due attention paid to full activation, as is found with prodrugs,
and to the worrying case of xenobiotic toxification.
Parts 6 and 7 cover the inter-individual and intra-individual
factors that influence drug metabolism, starting with an
introduction to evolutionary events leading to species differences
in the metabolism of xenobiotics and to polymorphisms within a
particular species. Focusing on humans, the most relevant
polymorphic drug-metabolizing enzymes are discussed, concentrating
on ethnic differences and on the consequences for the
pharmacokinetic behavior of affected drugs, while also introducing
sex-dependent metabolic reactions.
The final part introduces the mechanisms leading to increases or
decreases in enzyme activities as the concept of enzyme induction
via nuclear receptors and the different mechanisms of enzyme
inhibition are explained. With these basics in mind, various
influencing factors are discussed, including physiological and
pathological conditions, as well as drugs, nutrients and
environmental agents with a special focus on drug-drug
interactions.
With a foreword by Prof Leslie Z. Benet, the renowned
biopharmaceutical scientist.
General
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