Stereochemical Aspects of Drug Action and Disposition PDF
Preview Stereochemical Aspects of Drug Action and Disposition
Handbook of Experimental Pharmacology Volume 153 Edit or-in -Chief K. Starke, Freiburg i. Br. Editorial Board G.Y.R. Born, London M. Eichelbaum, Stuttgart D. Ganten, Berlin H. Herken, Berlin F. Hofmann, Miinchen L.E. Limbird, Nashville, TN W. Rosenthal, Berlin G. Rubanyi, Richmond, CA Springer-Verlag Berlin Heidelberg GmbH Stereochemical Aspects of Drug Action and Disposition Contributors S.K. Branch, C.M. Brett, P.-A. Carrupt, C. Dressler, M. Eichelbaum, G. Geisslinger K.M. Giacomini, D.IW. Grant, A. Gross, C.-H. Gu, P.I Hayball, K. Hostettmann, A.P. Ijzerman, G. Klebe, C. Leisen, D. Maule6n, IM. Mayer, R.I Ott, M. Reist, s. Rudaz, w. R.R. Shah, A. Somogyi, Soudijn, H. Spahn-Langguth, 1. Tegeder, C. Terreaux, B. Testa, C. Valenzuela, N.P.E. Vermeulen, I-L. Veuthey, P. Vogel, 1. van Wijngaarden, K. Williams Editors Michel Eichelbaum, Bemard Testa and Andrew Somogyi i Springer Praf. Dr. Michel Eichelbaum Dr. Margarete-Fischer-Bosch Institut fur Klinische Pharmakologie Auerbachstr. 112 70376 Stuttgart Germany e-mail: michel.eichelbaum@ikp-stuttgarLde Praf. Dr. Bernard Testa University of Lausanne School of Pharmacy 1015 Lausanne Switzerland e-mail: [email protected] Praf. Dr. Andrew Somogyi University of Adelaide Dept. of Clinical and Experimental Pharmacology 5005 Adelaide Australia e-mail: [email protected] With 96 Figures and 32 Tables ISBN 978-3-642-62575-6 ISBN 978-3-642-55842-9 (eBook) DOI 10.1007/978-3-642-55842-9 Cataloging-in-Publication Data applied for Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publica tion in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at <http://dnb.ddb.de>. This work is subject to copyright. All rights are reserved. whether the whole or part of the material is concerned. specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in other ways, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution act under German Copyright Law. http://www.springer.de © Springer-Verlag Berlin Heidelberg 2003 Originally published by Springer-Verlag Berlin Heidelberg New York in 2003 Softcover feprint of the hardcover lst edition 2003 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Typesetting: SNP Best-set Typesetter Ud., Hong Kong Cover-Design: design & production GmbH, Heidelberg Printed on acid-free paper 27/3020/kk 5 4 3 2 1 O Preface State-of-the-Art Chirality Stereochemistry in general and chirality in particular have long been recog nized as major structural factors influencing pharmacological activity and pharmacokinetic behavior. For more than a century, relevant information in these fields has been accumulating at an accelerating pace, leading to rationalizations, concepts and theories of increasing breadth and depth. Frequently, fundamental advances in stereochemical aspects of molecular pharmacology, drug disposition and pharmacochemistry have been translated into corresponding progress in clinical pharmacology and pharmacotherapy. There have been exceptions, however, since some extrapolations from the biochemical and in vitro situations to the in vivo human situation have proven premature. This notion resulted in the now appeased, but far from closed, debate regarding racemic versus enantiopure drugs, which saw some pro ponents state that "in many cases, only one isomer contributes to the thera peutic action while the other, the 'isomeric ballast', only contributes to the side effects and toxicity" (ARIENS 1986,1989,1992). Other authors, in contrast, have cautioned against hasty generalizations and advocated a more pragmatic, case by-case and evidence-based view (CALDWELL 1995; DE CAMP 1989; SZELENYI et al. 1998; TESTA 1991; TESTA and TRAGER 1990; TESTA et al. 1993). A survey conducted a few years ago (MILLERS HIP and FITZPATRICK 1993) found that the vast majority of natural and semisynthetic drugs are chiral and marketed as a single isomer. In contrast, only half of synthetic drugs are chiral, and among these more than half are marketed as the racemate. To avoid the complications of developing chiral drug candidates, some medicinal chemists give systematic preference to achiral compounds. This attitude is in sharp con trast with a global trend, clearly detectable in the pharmaceutical industry and its suppliers, to face head-on the synthetic, analytical, pharmacokinetic and pharmacological problems specific to enantiopure drugs, in a sustained effort towards innovation and originality; an approach which is built on current knowledge, but clearly requires a greater understanding of the complex stereochemical interplay between chemical/drug and body macromolecule that impacts at the pharmaco-dynamic, -toxicologic and -kinetic level (STINSON 1995, 1998, 1999,2000). VI Preface The results of such an approach have been inconsistent. For example, there are numerous instances of recognized therapeutic advantages to single isomeric drugs (HANDLEY 1999), not to mention commercial advantages when a patent granted to an enantiopure drug can replace an expiring patent to the racemate (AGRANAT and CANER 1999; STINSON 1997). These recognized or expected benefits have led to a number of "chiral switches", whereby chiral drugs marketed as racemates are redeveloped and marketed as single enan tiomers (i.e., as the eutomer). Successful examples include (R)-albuterol, (S)-omeprazole and (S)-ketamine. In contrast, the pharmaceutical industry is confronted with some chiral switches that have ended in failure and market recall. (R)-Fluoxetine and (S)-fenfluramine are respective examples of a pre- and post-marketing failure caused by unwanted and obviously unexpected side effects. These failures are all the more frustrating since the fundamental mechanisms underpinning such side effects remain poorly understood. In these cases, the pharmacodynamic and/or pharmacokinetic interactions between distomer and eutomer in the racemate may have prevented a side effect caused by the eutomer adminis tered alone; however, the mechanism(s) remain to be established. Clearly, the above paradigm could lead the community of drug researchers to the conclusion that the problem of racemic-versus-enantiopure drugs knows only exceptions and no rule. In a reaction against such a pessimistic and even defeatist attitude, we have accepted Springer's invitation to edit a monograph on the stereochemical aspects of drug action and disposition. To map both our vast knowledge and deep ignorance on the subject, we have been fortunate to receive the enthusiastic support of a number of col leagues whose combined expertise covers this multidisciplinary field. Quite naturally, the book spans the subject from the molecular to the clinical level. The first section on chemical aspects contains chapters on chemical synthesis, analysis, natural products, chiral stability (racemization) and physical prop erties. The second section is on experimental pharmacology, with chapters on drug-receptor interactions, chiral recognition, ion channels and molecular toxicology. The third section focuses on drug disposition, with chapters on absorption, distribution, protein binding, metabolism and elimination. The final section is dedicated to regulatory and clinical aspects. With such a broad yet structured monograph, we hope to convince our readers in the pharmaceutical and biotechnology industries and academia that there are reasons for both optimism and caution in investigating stereo isomeric drugs. When used as probes or as medicines, stereoisomeric drugs offer invaluable pharmacological insights or innovative therapeutic strategies. But because the compared pharmacological properties of racemates and enan tiomers remain incompletely understood, unexpected setbacks may occur which only systematic and dedicated research will render less probable. The book also conveys another, more implicit message, that stereochem istry is an essential dimension in pharmacology and should be understood as such by all drug researchers whatever their background. All too often indeed, Preface VII investigations are still being conducted and published that ignore the contri bution of stereochemistry to data interpretation and extrapolation of results to therapeutic implications (SOMOGYI 1998). ARIENS'S warning (1984) remains as valid now as it was almost two decades ago. By summarizing in a structured manner our current state of knowledge and ignorance on stereochemical aspects of drug action and disposition, this book aims to guide and inspire drug researchers as they enter the twenty-first century. MICHEL EICHELBAUM, BERNARD TESTA and ANDREW SOMOGYI References Agranat I, Caner H (1999) Intellectual property and chirality of drugs. Drug Disc Today 4:313-321 Ariens EJ (1984) Stereochemistry, a basis for sophisticated nonsense in pharmacoki netics and clinical pharmacology. Eur J Clin Pharmacol 26:663-668 ArieMns EJ (1986) Stereochemistry: a source of problems in medicinal chemistry. Med Res Rev 6:451--466 Ariens EJ (1989) Stereoselectivity in the action of drugs. Pharmacol ToxicoI64:319-320 Ariens EJ (1992) Racemic therapeutics: a source of problems to chemists and physi cians. Anal Proceed 29:232-234 Caldwell J (1995) "Chiral pharmacology" and the rcgulation of new drugs. Chern Ind 176-179 De Camp WH (1989) The FDA perspective on the development of stereoisomers. Chirality 1:2-6 Handley DA (1999) The therapeutic advantages achieved through single-isomer drugs. Pharm News 6:11-15 Millership JS, Fitzpatrick A (1993) Commonly used chiral drugs: a survey. Chirality 5:573-576 Somogyi A (1998) Stereoselectivity in drug disposition. Naunyn-Schmiederberg's Arch Pharmacol 358[Suppl 2]:R760 Stinson SC (1995) Chiral drugs. Chern Eng News 73:44-74 Stinson SC (1997) FDA may confer new status on enantiomers. Chern Eng News 75:28-29 Stinson SC (1998) Counting on chiral drugs. Chern Eng News 76:83-104 Stinson SC (1999) Chiral drug interactions. Chern Eng News 77:101-120 Stinson SC (2000) Chiral drugs. Chern Eng News 78:55-78 Szelenyi I, Geisslinger G, Polymeropoulos E, Paul W, Herbst M, Brune K (1998) The real Gordian knot: racemic mixtures versus pure enantiomers. Drug News Persp 11:139-160 Testa B (1991) Editorial-Stereophilia. Drug Metab Rev 24:1-3 Testa B, Trager WF (1990) Racemates versus enantiomers in drug development: dogmatism or pragmatism? Chirality 2:129-133 Testa B, Carrupt PA, Christiansen LH, Christoffersenp, Reist M (1993) Chirality in drug research: stereomania, stereophobia, or stereophilia? In: Claassen V (ed) Trends in receptor research. Elsevier, Amsterdam, pp 1-8 List of Contributors BRANCH, S.K., Medicines Control Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, SW8 5NQ, UK BRETT, CM., Department of Anesthesia, 521 Parnassus Auenue Room C-450, Box-0648 San Francisco California 94143-0648, USA e-mail: [email protected] CARRUPT, p.-A., Institut de Chimie Therapeutique, BEP, Universite de Lausanne, 1015 Lausanne-Dorigny, Switzerland DRESSLER, C, Martin-Luther-Universitat Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeck-Str. 4, 06120 Halle Saale, Germany EICHELBAUM, M., Dr. Margarete-Fischer-Bosch-Institut fur Klinische Pharmakologie, Auerbachstrasse 112, 70376 Stuttgart, Germany e-mail: [email protected] GEISSLINGER, G., Fachbereich Humanmedizin, Zentrum der Pharmakologie, University of Frankfurt, 60596 Frankfurt am Main, Germany e-mail: [email protected] GIACOMINI, K.M., Department of Biopharmaceutical Sciences, UCSF Box 0446, University of California, San Francisco, CA 94143-0446, USA e-mail: [email protected] GRANT, D.J.W., Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455-0343, USA e-mail: [email protected]. umn.edu GROSS, A., Clinical Pharmacology and Discovery Medicine, GSK R&D, James Lance GlaxoSmithkline Medicines Research Unit, Prince of Wales Hospital Randwick, NSW, 2031, Australia e-mail: [email protected] x List of Contributors Gu, C.-H., 1 Squibb Drive, P.o. 191, Bristol-Myers Squibb, New Brunswick, NJ 08903, USA e-mail: [email protected] HAYBALL P.I, School of Pharmaceutical, Molecular & Biomedical Sciences, City East Campus, Reid Building Frome Road, Adelaide 5000, South Australia e-mail: [email protected] HOSTETIMANN, K., Institute of Pharmacognosy and Phytochemistry, BEP, University of Lausanne, 1015 Lausanne, Switzerland e-mail: [email protected] IJZERMAN, A.P., Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, PO Box 9502,2300 RA Leiden, The Netherlands e-mail: [email protected] KLEBE, G., Philipps-Universitat Marburg, Institut fUr Pharmazeutische Chemie, Marbacher Weg 6, 35032 Marburg, Germany e-mail: [email protected] LEISEN, c., Martin-Luther-Universitat Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeck-Str. 4, 06120 Halle/Saale, Germany D. MAULEON, D., Development Team Consulting S.L., via Augusta 59, of 302, 08006 Barcelona, Spain MAYER, 1M., Institut de Chimie Therapeutique, BEP, Universite de Lausanne, 1015 Lausanne-Dorigny, Switzerland OTI, R.I, GlaxoSmithkline Research and Development, Five Moore Drive, PO Box 13398 Research Triangle Park, NC 27709-3398, USA e-mail: [email protected] REIST, M., Institut de Chimie Therapeutique, BEP, Universite de Lausanne, 1015 Lausanne-Dorigny, Switzerland RUDAZ, S., Laboratory of Pharmaceutical Analytical Chemistry, University of Geneva, 20 Bd d'Yvoy, 1211 Geneva 4, Switzerland SHAH, R.R., Medicines Control Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, SW8 5NQ, UK e-mail: [email protected] SOMOGYI, A., Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide 5005, Australia e-mail: [email protected] List of Contributors XI Soudijn, W., Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, PO Box 9502, NL-2300 RA Leiden, The Netherlands SPAHN-LANGGUTH, H., Martin-Luther-University Halle-Wittenberg, Department of Pharmaceutical Chemistry, Wolfgang-Langenbeck-Strasse 4, 06120 Halle/Saale, Germany e-mail: [email protected] TEGEDER, 1., Universitatsklinikum Frankfurt Haus 75/4. OG Theodor-Stern Kai 7 60590 Frankfurt/Main, Germany e-mail: [email protected] TERREAUX, c., Institute of Pharmacognosy and Phytochemistry, BEP, University of Lausanne, 1015 Lausanne, Switzerland TESTA, B., Institut de Chimie Therapeutique, BEP, Universite de Lausanne, 1015 Lausanne-Dorigny, Switzerland e-mail: [email protected] VALENZUELA, c., Institute of Pharmacology and Toxicology, CSIClUCM, School of Medicine, Universidad Complutense, 28040 Madrid, Spain e-mail: [email protected] VERMEULEN, N.P.E., Division of Molecular Toxicology, Department of Pharmacochemistry, De Boelelaan 1083,1081 HV Amsterdam, The Netherlands e-mail: [email protected] VEUTHEY, l-L., Laboratory of Pharmaceutical Analytical Chemistry, University of Geneva, 20 Bd d'Yvoy, 1211 Geneva 4, Switzerland e-mail: [email protected] VOGEL, P., Section de Chimie de L'Universite de Lausanne, BCH, 1015 Lausanne-Dorigny, Switzerland e-mail: [email protected] VAN WUNGAARDEN, 1., Leiden/Amsterdam, Center for Drug Research, Division of Medicinal Chemistry, Leiden University, PO Box 9502, NL-2300 RA Leiden, The Netherlands WILLIAMS, K., Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, University of New South Wales, Darlinghurst 2010, Australia e-mail: [email protected]
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