Importance of Drug Metabolism in Drug Discovery and Development

  • Rodolfo Gasser
Part of the NATO ASI Series book series (NSSA, volume 303)


The metabolism of a drug can have important consequences on its therapeutic effect or its toxicity. For this reason, early assessments of metabolic pathways in man help to foresee interindividual variation in drug response and elimination due to metabolism. To address these issues, in vitro techniques based on human material are increasingly used as the basis for rational decisions during drug selection and development and to assess risk and potential drug interactions in man.


Drug Metabolism Human Liver Microsome P450 Reductase Human Liver Cytochrome Enzyme Kinetic Analysis 
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  1. 1.
    W. Kalow, 1993, Pharmacogenetics: Its biological roots and the medical challenge, Clin Pharmacol Ther, 54:235–241.PubMedCrossRefGoogle Scholar
  2. 2.
    L.M. Dislerath, F.P. Guengerich, 1994, Enzymology of human liver cytochrome P-450, in: Mammalian Cytochmmes P-450, Volume 1 (F.P. Guengerich, ed.) pp. 133–198, CRC Press, Boca Raton, Florida.Google Scholar
  3. 3.
    F.P. Guengerich, 1987, Cytochrome P-450 and drug metabolism, Progress in Drug Melab. 10:1–44.Google Scholar
  4. 4.
    A.D. Rodrigues, 1994, Use of in vitro human metabolism studies in drug development, Biochem. Pharma col. 48:2147–2156.CrossRefGoogle Scholar
  5. 5.
    R.P. Remmel and B. Burchell, 1993, Validation and use of cloned, expressed human drug metabolizing en zymes in heterologous cells for analysis of drug metabolism and drug-drug interactions, Biochem. Pharma col. 46:559–566.CrossRefGoogle Scholar
  6. 6.
    A. Wiseman, 1993, Genetically-engineered mammalian cytochromes P-450 from yeast-potential applica tions. TIBTECH 11:131–136.CrossRefGoogle Scholar
  7. 7.
    J. Doehmer, W.A. Schmalix and H. Greim, 1994, Genetically engineered in vitro systems for biotransfor mation studies, Meth. Exp. Clin. Pharmacol. 16:513–518.Google Scholar
  8. 8.
    J.A.R. Blake, M. Pritchard, S. Ding, G.C.M Smith, B. Burchell, C.R. Wolf and T. Friedberg, 1996, Coex-pression of a human P450 (CYP3A4) and P450 reductase generates a highly functional monooxygenase system in Escherichia coli, FEBS Lett. 397:210–214.PubMedCrossRefGoogle Scholar
  9. 9.
    T. Omura and R. Sato, 1964, The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem. 239:2370–2378.PubMedGoogle Scholar
  10. 10.
    T. Kronbach, D. Mathys, M. Umeno, F.J. Gonzales and U.A. Meyer, 1989, Oxidation of midazolam and triazolam by human liver cytochrome P450IIA4. Mol. Pharmacol. 36:89–96.PubMedGoogle Scholar
  11. 11.
    M. Shou, J. Grogan, J.A. Mancewicz, K.W. Krausz, F.J. Gonzalez, H.V. Gelboin and K.R. Korzekwa, 1994, Activation of CYP3A4: Evidence for the Simultaneously Binding of Two Substrates in a Cytochrome P450 Active Site, Biochemistry 33:6450–6455.PubMedCrossRefGoogle Scholar
  12. 12.
    C. Peck, R.T. Temple and J.M. Colllins, 1993, Understanding consequences of concurrent therapies, JAMA, 269:1550–1552.PubMedCrossRefGoogle Scholar
  13. 13.
    A.H. Conney, E.C. Miller, J.A. Miller, 1956, The metabolism of methylated amino dyes. Evidence for in duction of enzyme synthesis in the rat by 3-Methylcholanthrene. Cancer Research 16:450–459.PubMedGoogle Scholar
  14. 14.
    H. Remmer, H.J. Merker, 1963, Drug induced changes in the liver endoplasmic reticulum: association with drug metabolizing enzymes, Science 142:1657–1658.PubMedCrossRefGoogle Scholar
  15. 15.
    B.K. Park, A.M. Breckenridge, 1981, Clinical implications of enzyme induction and enzyme inhibition, Clin. Pharmacokinet. 6:1–24.PubMedCrossRefGoogle Scholar
  16. 16.
    A.B. Okey, 1990, Enzyme induction in the cytochrome P-450 system, Pharmac. Ther. 45:241–298.CrossRefGoogle Scholar
  17. 17.
    A.R. Boobis, D. Sesardic, B.P. Murray, R. J. Edwards, A.M. Singleton, K.J. Rich, S. Murray, R. de la Torre, J. Segura, O. Pelkonen, 1990, Species variation in the response of the cytochrome P-450 dependent monooxygenase system to inducers and inhibitors, Xenobiotica 20:1139–1161.PubMedCrossRefGoogle Scholar
  18. 18.
    C. Ged, J.M. Rouillon, L. Pichard, J. Lombalbert, N. Bressot, P. Bories, H. Michel, P. Beaune, P. Maurel, 1989, The increase in urinary excretion of 6ß-hydroxycortisol as a marker of human hepatic cytochrome 3A induction. Br. J. Clin. Pharmacol. 28:373–387.PubMedCrossRefGoogle Scholar
  19. 19.
    W. Kalow, B.K. Tang, 1991, Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase ac tivities. Clin. Pharmacol. Ther. 50:508–519.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Rodolfo Gasser
    • 1
  1. 1.F. Hoffmann-La RocheBaselSwitzerland

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