Perspectives in drug–drug interactions

Abstract

Drug–Drug InteractionsEdited by A. David Rodrigues. Marcel Dekker Inc., 2002. US$195.00 hbk (xii + 585 pages) ISBN 0 8247 0283 2This monograph provides an extensive and detailed review of state-of-the-art knowledge and methods to explore and predict the drug–drug interaction potential of drug development candidates. Each chapter is written by an expert in the field. The book mainly focusses on drug interactions in the area of drug metabolism and disposition. Although these areas are by far the most relevant concerning observed clinically relevant drug interactions, the title is thus somewhat misleading. The objective, however, to broadly cover the complete field of research and to present the subject from various perspectives has been achieved successfully.Chapters 1, 2 and 3 are mainly introductory and cover pharmacokinetic and pharmacodynamic concepts, in vitro enzyme kinetic principles and the role of human cytochrome-P450s in drug metabolism. Chapter 4 is very specific and reminds the experienced reader that there is more than cytochrome P450 – but it is debatable if such a review can or must cover everything!Chapters 5 to 10 are excellent up-to-date reviews of current in vitro techniques to elucidate the cytochrome P450 isozymes involved in drug metabolism or transporters, such as P-glycoprotein (PgP), involved in drug disposition and how to identify drug–drug interaction potential using sophisticated in vitro approaches. Chapter 5 describes currently known transporter systems and examples of transporter mediated interactions: the tables provide an excellent overview of this rapidly expanding field.Chapter 6, focusses on primary hepatocyte cultures as the most important in vitro model used. Based on the author's own broad experience schematic experimental protocols are provided, suitable endpoints and parameters are discussed and the importance of species differences is highlighted. In vitro approaches to predict the most important cause of pharmacokinetic drug–drug interactions, inhibition of drug metabolizing enzymes, are covered in Chapter 7. This excellent chapter includes a comprehensive overview of the theoretical concepts, and discusses all relevant in vitro approaches currently used for both study types. The detailed recommendations for the experimental study design as well as the numerous practical hints including potential pitfalls provide valuable guidance also for the experienced reader. PgP, the best investigated transporter system to date, is covered specifically in Chapter 8. Chapter 10 focusses on the pharmacokinetic implications of this special case. The authors provide the reader with the basic principles to calculate in vitro estimates of pharmacokinetic constants and their use for the prediction of in vivo interactions.The second part of the book, about the various aspects of the in vivo consequences, starts with the predictivity of in vivo metabolic drug interactions. Similar to Chapter 15, which describes the clinical perspectives of drug–drug interactions, the reviews are brief and not completely successful in making their point. Chapter 12 is an extensive review of clinical pharmacological study designs in investigating drug interactions but clear proposals how to proceed are lacking. The chapter about the regulatory perspective summarizes the recent publications of the authors and reflects the excellent Food and Drug Administration guidelines issued on the topic of metabolic drug–drug interactions.Chapter 13 is an interesting chapter for the advanced reader on the status of predicting cytochrome P450-mediated drug metabolism from molecular structure information. The marketing perspective is given in discussions of the market withdrawals of terfenadine and mibefradil, and the market situation of cimetidine. In this section a more extended text on post-marketing surveillance of drug–drug interactions, its problems, chances, failures and successes would have been more helpful.Overall, this is a well referenced and up-to-date volume and there is something in this book for everybody involved in discovering and predicting the drug–drug interaction potential of new drugs under development.