Book Reviews

Drug Metabolism Databases and High-Through-put Testing During Drug Design and Develop-ment. Edited by Paul W. Ehrhardt. InternationalUnion of Pure and Applied Chemistry, Blackwell Sci-ence, Ltd., Malden, MA. 1999. 340 pp. 19 x 25 cm. ISBN0-632-05342-9. $60.00.

This book is the result of deliberations of a WorkingParty of the IUPAC, assembled to consider the topicMetabolism Databases and Their Potential Utility in theDevelopment of New Drugs. Paul Ehrhardt, the techni-cal editor for this volume, was the chair of the WorkingParty. His introduction provides a historical perspectiveand highlights some of the biological considerations thatcontribute to poor predictability of drug metabolism inhumans. The book is arranged in three sections. Thefirst contains several historical case studies describingthe use of metabolism expert systems or databases inthe pharmaceutical industry. The middle section con-tains monographs on various techniques for high-throughput screening of drug candidates, descriptionsof ex vivo models of drug metabolism, and chapters onthe use of metabolism databases in drug design. Thefinal section of the book, entitled Emerging Products,contains contributions from vendors of commercialproducts. Expert systems and metabolism databases aredescribed briefly. The appendix contains tables of com-mercially available drug metabolism databases andcontract research organizations that conduct high-throughput screening. A glossary is also provided.

The first section of the book, Case Studies, is well-balanced and provides thought provoking and enter-taining examples of the utility of various databasesavailable from 1985-1995. Several evaluations of theeffectiveness of expert systems to predict drug metabo-lism are presented. Specific drug examples from indus-trial scientists illustrate the difficulty of prediction andindicate the difficulties in quantitative prediction with"expert" systems. Descriptions of searchable metabolismdatabases used at Parke-Davis, Eli Lilly, and Baeyerprovide clear examples of what information should beincluded in these databases. However, a chapter sub-mitted from Daiichi Pharmaceutical consists almostentirely of metabolic schemes for two drugs and adiscussion is missing. The section ends with a chapteron the design and development of two prodrugs, esmololand imidazolone, but this seems out of place with theprevious chapters.

The organization of the middle section of the book isdisjointed. The first chapter describes the determinationof drug permeability of the Caco-2 colon cell line forprediction of gastrointestinal absorption and would havebeen more logically placed with the other chapters onhigh-throughput screening. Unfortunately, the use ofthe Caco-2 system to study the role of intestinaltransporters and efflux pumps such as P-glycoprotein

in drug absorption is not included in this chapter. Thissection includes a chapter on preclinical drug metabo-lism screening, screening for inhibition of P-450 me-tabolism, and pharmacokinetic screening by the N-in-one (cassette dosing) technique. These chapters are well-written, and they critically evaluate the techniques andproblems arising from high-throughput screening.

The second chapter in the section the contains alengthy introduction on the cytochrome P450 system.This may be useful to novices in the drug metabolismfield, but the rest of the book appears to be targeted toa more knowledgeable audience. The second half of thechapter describes the administration of a drug cocktailconsisting of several individual P450 enzyme substratesto predict the clearance of drugs in an individualthrough a “handprint strategy”. This material does notrelate to either high-throughput screening or ex vivomodels of drug metabolism. A commentary on theimportance of developing databases of drug interactions(by using antiepileptic drug examples) would have beenmore logically placed after the high-throughput screen-ing chapters. Three short chapters on model systemsto predict P450-mediated metabolism are located be-tween chapters on high-throughput screening of drugmetabolism. Chapters on the use of microorganisms asmodel systems of drug metabolism and synthetic met-alloporphyrins as P450-like catalysts highlight otherexperimental techniques for ex vivo prediction of oxida-tive metabolism.

An interesting chapter describes the use of a databasecalled the Encyclopedia of E. coli Genes and Metabolism(EcoCyc) used to identify novel targets for antimicrobialdrug discovery. The section ends with more traditionaldiscussions of the use of metabolism databases to designprodrugs and codrugs and the design of soft drugs.

The final section of the book was written by severalcommercial vendors (not associated with the IUPACWorking Group) and describes products such as Metab-polExpert, META, and Metabolite. Descriptions of twometabolic databases from Synopsys and LHASA UK,Ltd. are included. These chapters are brief and descrip-tive in nature, but along with the appendix will beuseful for those in the pharmaceutical industry who areinterested in a general overview of the currently avail-able products.

The potential audience for this book lies primarily inthe pharmaceutical industry. This compendium wouldbe a very useful starting point for those involved in datamanagement of drug metabolism results, although achapter or two from experts in bioinformatics mighthave been an interesting addition to the book. Theindividual monographs are not highly detailed andindividuals involved in programming and databasemanagement will use the book primarily as a source forreference citations. Academic libraries that supportgroups of researchers in drug metabolism or drugdiscovery may wish to obtain this volume of the IUPACseries, but the book should not be considered as a

Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3197

reference text in drug metabolism, nor can this reviewerforesee its use as a textbook. The volume is well-editedand contains very few typographical errors. This volumeachieves its goal as a broadly based introduction to theapplication of drug metabolism databases to drugdiscovery.

Rory P. Remmel

Department of Medicinal ChemistryUniversity of Minnesota

Minneapolis, Minnesota 55455

JM000236D

10.1021/jm000236d

3198 Journal of Medicinal Chemistry, 2000, Vol. 43, No. 16 Book Reviews