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Inside the drug industry
TiPS - August 2990 /Vol. 7 11
Comparing conjugation reactions in vivo and in vitro Conjugation Metabolism: Approach
Reactions in Drug An Integrated
edited by Gerard 1. Mulder, Taylor & Francis, 1990. E49.00 (413 pages) ISBN 0 85066 738 0
One of the main problems facing toxicologists and others involved in safety evaluations of drugs is the extrapolation of data obtained in animals to humans. The traditional approach - applying safety factors and simply trying low doses - has increasingly become tiresome. Moreover, most drugs recently taken off the market have suffered this fate because of an unusual reaction sequence only occurring (or only occurring to that extent) in humans. Usually biotransformation is heavily involved in this process. The metabolic fate of a given drug is determined by complex interactions of numerous drugmetabolizing enzymes. The ratio of activities of the various pathways is determined firstly by the tissue/cellular distributions of the enzymes. For humans, genetic deficiencies of certain pathways have been recognized as an important factor in this regard. Secondly, subtle factors governing the differences in substrate selectivity from one species to another play a role. Yet there is hope: almost all biotransformation pathways occur to some extent in all species, and although differences are significant, they are more usually a question of distribution (i.e. availability of the right amounts of a given enzyme) than of differences in affinity for a given substrate. This allows the possibility of taking a ‘detour’ in the extrapolation process with the aim of arriving at the finish feeling a little safer than after the short, straight, old-fashioned route. Varinus reactions known to occur in experimental animals can be studied in vitro; these data can thcrl be compared
339
with human in vitro data, and only when this comparison gives the right result (whatever that may be: either the absence or the presence of a particular pathway might be beneficial), is the step to the human in vivo experiment taken. In practice, biotransformation is divided into two areas: phase 1 and phase 2 reactions, or transformations (of which oxidation is the most important) and conjugations. Recently considerable progress has been made in comparing in vitro with in uivo data for oxidation reactions, and numerous reviews on this subject have appeared. The present book deals with conjugatibn reactions,
Anatomy of a pharmaceutical company Inside the Drug Industry by Bert Spilker and Pedro CuntreProus Science Publishers, 2990. $15.00 (xvii + 109 pages) iSBN 84 86973 22 8
casas,
Pharmaceutical companies comprise three branches: research, development, and marketing and manufacturing. The research department seeks new compounds to treat a disease based on its
and will no doubt prove a useful tool in the extrapolation process described above. The objective of comparing in vivo with in vitro data for a whole series of conjugating enzymes is an admirable one. The first part of the book deals with kinetics (a very nice chapter by K. S. Pang) and competition between various conjugating enzymes, both ifr vivo. Then all other conjugation reactions are represented in chapters written by undisputed experts in their fields. Each chapter deals with both enzymes and cofactors both in vitro and in vivo. This book certainly deserves a wide audience, and the approach it represents deserves repeating. PETER J. VAN BLADEREN TNO-CWO Toxicdog!/ nd Nzctrifim I&if&, Utrechtscweg 4X,3701 HE Z&t, NrtkrIl7WiS.
pathenogenetic mechanism. For one compound to make it to market, an average of 10000 new compounds must be synthesized and tested, with only the best of these moving on to development. Development’s job is to transform the compound into a drug First comes ‘toxicology’; if chronically treated animals show no adverse effects, the pharmaceutical company files with the Food and Drug Administraiion (FDA) fcr an ‘Investigational New Drug Exemption’ (IND). Subsequently sideeffects and pharmacokinetics are determined in normal human
Comparing conjugation reactions in vivo and in vitro Conjugation Metabolism: Approach
Reactions in Drug An Integrated
edited by Gerard 1. Mulder, Taylor & Francis, 1990. E49.00 (413 pages) ISBN 0 85066 738 0
One of the main problems facing toxicologists and others involved in safety evaluations of drugs is the extrapolation of data obtained in animals to humans. The traditional approach - applying safety factors and simply trying low doses - has increasingly become tiresome. Moreover, most drugs recently taken off the market have suffered this fate because of an unusual reaction sequence only occurring (or only occurring to that extent) in humans. Usually biotransformation is heavily involved in this process. The metabolic fate of a given drug is determined by complex interactions of numerous drugmetabolizing enzymes. The ratio of activities of the various pathways is determined firstly by the tissue/cellular distributions of the enzymes. For humans, genetic deficiencies of certain pathways have been recognized as an important factor in this regard. Secondly, subtle factors governing the differences in substrate selectivity from one species to another play a role. Yet there is hope: almost all biotransformation pathways occur to some extent in all species, and although differences are significant, they are more usually a question of distribution (i.e. availability of the right amounts of a given enzyme) than of differences in affinity for a given substrate. This allows the possibility of taking a ‘detour’ in the extrapolation process with the aim of arriving at the finish feeling a little safer than after the short, straight, old-fashioned route. Varinus reactions known to occur in experimental animals can be studied in vitro; these data can thcrl be compared
339
with human in vitro data, and only when this comparison gives the right result (whatever that may be: either the absence or the presence of a particular pathway might be beneficial), is the step to the human in vivo experiment taken. In practice, biotransformation is divided into two areas: phase 1 and phase 2 reactions, or transformations (of which oxidation is the most important) and conjugations. Recently considerable progress has been made in comparing in vitro with in uivo data for oxidation reactions, and numerous reviews on this subject have appeared. The present book deals with conjugatibn reactions,
Anatomy of a pharmaceutical company Inside the Drug Industry by Bert Spilker and Pedro CuntreProus Science Publishers, 2990. $15.00 (xvii + 109 pages) iSBN 84 86973 22 8
casas,
Pharmaceutical companies comprise three branches: research, development, and marketing and manufacturing. The research department seeks new compounds to treat a disease based on its
and will no doubt prove a useful tool in the extrapolation process described above. The objective of comparing in vivo with in vitro data for a whole series of conjugating enzymes is an admirable one. The first part of the book deals with kinetics (a very nice chapter by K. S. Pang) and competition between various conjugating enzymes, both ifr vivo. Then all other conjugation reactions are represented in chapters written by undisputed experts in their fields. Each chapter deals with both enzymes and cofactors both in vitro and in vivo. This book certainly deserves a wide audience, and the approach it represents deserves repeating. PETER J. VAN BLADEREN TNO-CWO Toxicdog!/ nd Nzctrifim I&if&, Utrechtscweg 4X,3701 HE Z&t, NrtkrIl7WiS.
pathenogenetic mechanism. For one compound to make it to market, an average of 10000 new compounds must be synthesized and tested, with only the best of these moving on to development. Development’s job is to transform the compound into a drug First comes ‘toxicology’; if chronically treated animals show no adverse effects, the pharmaceutical company files with the Food and Drug Administraiion (FDA) fcr an ‘Investigational New Drug Exemption’ (IND). Subsequently sideeffects and pharmacokinetics are determined in normal human