From the author perspective, it is understood that for decades, drug metabolism has been an area of pharmacology that has been interesting in its own right, drawing on the instrumental expertise of analytical chemistry, the elegance of enzymology, and the emerging tools of molecular biology. While serving its primary role as an independent discipline, drug metabolism has also produced a number of important contributions to the development and therapeutics of specific agents.
Drug-Drug Interactions: Scientific and Regulatory Perspective In the area of pharmacogenetics, several deficiencies of drug-metabolizing enzymes have been reported (e.g., N-acetyltransferase for metabolism of isoniazid). Interactions between coadministered drugs have been described based on either induction of the metabolizing enzymes (e.g., by anticonvulsants) or inhibition (e.g., quinidine and CYP2D6).
As the variety of new drugs has increased and polypharmacy has become commonplace, drug-drug interactions have been gaining in visibility. In less than five years, we have seen an impressively swift change in the paradigm of applications for these studies. All of the elegance and academic interest remain, but there is also a fundamental retargeting of efforts toward predictive approaches rather than retrospective evaluations. Although the identification of metabolic pathways is still a central event for each new drug, there is an immediate emphasis on interpreting these pathways in terms of understanding, anticipating, and avoiding adverse drug-drug interactions. As described in this volume, the set of tools is impressively arrayed for the exploration of metabolic-based interactions, ranging from the classics of microsomes, hepatocytes, or slices, and then intersecting with the realm of molecular biology via recombinant human enzymes and transgenic animal systems.
The organized ventures that procure, process, and distribute human-derived material have overcome the major barriers of availability that hindered past studies. However, this large tool chest in itself does not produce data that are useful to drug development and regulation. The users of the tools, clinical pharmacologists in academia, industry, and regulatory agencies, must focus on those experiments that yield the greatest insight into therapeutics. Once a drug-drug metabolic interaction has been discovered, the implications for further development and regulation can follow one of several scenarios. Most drug-drug interactions change the therapeutic index of one or both agents.
In general, we are concerned about either loss of therapeutic effect or amplification of adverse effects. However, not all interactions are automatically problematic. A few are even intentional, such as the treatment of methanol poisoning with ethanol. Either the parent drug or its metabolite(s) may have therapeutic and/or undesirable pharmacological effects. Thus, the interpretation of the consequences for an interaction depends on the relative therapeutic index of each pharmacologically active species. For example, if the parent compound has a more desirable therapeutic index than the metabolite, then inhibition might be advantageous (although the dose probably needs to be lowered). On the other hand, induction of metabolism of the parent to the metabolite could adversely affect therapy in this situation.
The task of applied methodology development is not complete. By far the greatest gains have come with the family of cytochrome P450 enzymes. We need to develop a similar level of sophistication and to apply the same principles to other reactions of therapeutic interest, such as the various transferases of Phase 2 metabolism. While the most recent work has focused on the evaluation of drugs as potential inhibitors of major metabolic pathways, promising work has also been reported on approaches to evaluating whether a new agent has the potential to induce the metabolism of itself and/or other concomitantly administered drugs.
Overall, the chapters in this book present a comprehensive review of the scientific and regulatory aspects of drug-drug interactions from the point of view of academia, industry, and government agencies. The topics covered include drug metabolism enzymes, toxicology, and in vitro mechanistic approaches, as well as the regulatory perspectives of drug-drug interactions. This book is intended for professionals in the pharmaceutical industry and in the healthcare and governmental regulatory agencies who are interested in the mechanistic understanding of drug-drug interactions, the prediction of the drug drug interaction potential of new drugs, and the avoidance of clinically significant drug-drug interaction in patients. This book should be of interest as well to students and researchers in the areas of pharmacology, toxicology, pharmacokinetics, and medicine.