Abstract
There are 2 fundamental requirements that permit xenobiotics to exert their therapeutic or toxic effects on living systems. The most important requirement is the intrinsic property to interact with a host organism’s receptor. Without the ability of a chemical to act as a ligand and interface with a receptor, there is neither therapy nor toxicity. However, even with an innate ability for a chemical to interact with a host’s receptor, there is no assurance that either beneficial or adverse effects in and for the host unless the chemical ligand can get to the site of the host’s receptor. Drug Metabolism in Diseases addresses the “when,” “how,” and at times, the “why” the disease state in the host influences, not the intrinsic ability of a chemical to interact with a receptor, but the ability and duration of a receptor–ligand interaction to occur. Much of the ability for the receptor–ligand interaction to occur is regulated by metabolic processes such as biotransformation and transporting mechanisms. Consequently, undertaking the study of the metabolism of a drug in the disease state is important for both the drug’s therapeutic benefits and understanding the detoxification process for the drug once it is no longer needed.
The book has over 270 pages of topical content, which is distributed among 11 chapters, 9 pages of prelim, and a 4-page index. The chapters are authored by 23 contributors. The sole editor contributed to 2 of the 11 chapters. There are 2 themes or consistencies that permeate the chapters. The most obvious consistency is the structural format of each chapter consisting of an introduction, a topical treatment, conclusion or summary, and a reference list. The not-so-obvious theme running through the chapters are the roles that receptors and genetics play in the convergence of disease and the metabolism of xenobiotics and the fluctuating interface between them. These themes not only echo the necessity but also provide the path for creating a greater alignment between therapeutic development and toxicity evaluation of drugs for the sake of greater economic efficiency. 1
The first chapter, “Introduction of Drug Metabolism and Overview of Disease Effect on Drug Metabolism” sets the stage with a soft and generic treatment of drug metabolism and the subsequent topics of metabolism of drugs in the disease conditions in the various chapters that follow. It is not a chapter for those looking for an introduction to drug metabolism; rather, the chapter serves as a filter for seeing the possible influences that a disease condition could have on drug metabolism.
The second and third chapters, which collectively constitute the major segment (17%) of the book, address the generic, nondisease-specific influence of inflammation on drug metabolism. The chapters address, separately, the influence of inflammation on drug metabolizing enzymes and drug transporters. The chapters are out of order for those readers searching for a logical flow in the book, the lack of which will be annoying to some readers.
Chapters 4, 6, and 7 address drug metabolism in kidney disease, cardiovascular disease, and type 2 diabetes mellitus. The remaining chapters, 5, 8, 9, 10, and 11, focus on drug metabolism in critical care, pediatric patients, pregnancy, estrogen metabolism enzymes in systemic and local liver injuries, and energy metabolism. By the chapter titles, one can see that the editor has a liberal view of “disease.”
Drug Metabolism in Diseases brings into focus 2 expansive concepts: (1) the absorption, distribution, biotransformation, and excretion of drugs and (2) a theoretically infinite number of conditions in which perpetual non-homeostasis exists and recognized as a disease state. Consequently, it is not surprising that the task to identify the most important issues for these 2 arenas is not simple. Should the selection of a metabolic topic to be addressed first in diseased conditions or should a specific disease be selected and examined to determine where the disease has caused a perturbation in the metabolic process for a drug? Where should the emphasis be placed: on drug metabolism or on the disease? This is not a simple question with simple answer, but rather a matter of choice.
The editor and the contributing authors took a combination or varied approach that gives the impression of ambivalence or inconsistency, for example, chapter 4—“Drug Metabolism in Kidney Disease” and chapter 2—“Regulation of Drug-Metabolizing Enzymes and Drug Metabolism by Inflammatory Responses.” In fairness to the editor and the authors, the universal treatment of the topic of metabolism of drugs in diseased, that is, all drugs and all diseases, exceeds the scope of 1 book. Perhaps a more appropriate title for the book might be found in a common theme such as biotransformation of drugs as a function of disease or diseases the affect drug transporters.
Clearly, the book is an important addition to a library but at the purchase price and the narrow topical treatment, the breadth of the title notwithstanding, will limit the book’s addition to a toxicologist’s personal library unless a toxicologist is actively engaged in drugs associated with the diseases that the book addresses. Perhaps the real value of the book is bequeathed to the nontoxicologists who are developing drugs for diseases and would serve as a common ground for both clinicians and toxicologists.
Finally, the enormity and complexity of addressing xenobiotic metabolism in any diseased state are not only important but vital to the patient with the misfortune of having the disease. In addition, subsets of the population, for example, age-related population segments, may be predisposed to metabolizing xenobiotics that would fit into the paradigm of “Personalized Medicine.” Data mining in many –omics research efforts seems to potentially have a home in addressing xenobiotic metabolism in individuals; call it “Personalized Detoxification.” However, rather than genetic criteria, published drug metabolism experimental results when the drug was studied in diseased condition would serve as selection criteria for the mining process. The foundation has been laid by Ananiadou, Kell, and Tsujii 2 in their paper describing text mining for developing programs in systems biology. While their paper is over 10 years old, toxicology and xenobiotic metabolism are now ready, thanks to Drug Metabolism in Diseases, to consider text mining for understanding how a xenobiotic changes a human and, from the metabolic point of view, how a human changes the xenobiotic. Personalized Medicine with its therapy focus has found a partner in Personalized Detoxification whose emphasis is on drug safety under the aegis of Drug Metabolism in Diseases.
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