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The Role of Biotransformation Studies in Reducing Drug Attrition

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Reducing Drug Attrition

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 11))

Abstract

Biotransformation has evolved beyond simple structural elucidation of metabolites to provide data that is highly impactful and influential to various aspects of drug discovery. Based on our experience, we have grouped areas where biotransformation-related understanding can make an impact on drug design as follows: (1) defining clearance mechanisms, particularly for drug metabolizing enzymes other than P450s, (2) identifying metabolic hot spots, (3) identifying reactive metabolites, (4) characterizing active metabolites, and (5) assessing metabolite safety. This review will describe how these studies may be used to guide the development of structure–activity relationships to identify and mitigate potential safety liabilities and to interpret pharmacokinetic/pharmacodynamic (PKPD) relationships. Ultimately, a better understanding in all these aspects of drug disposition will aid in reducing candidate attrition.

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Authors and Affiliations

  1. Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research & Development, 1 Eastern Point Road, Groton, CT, 06340, USA

    Douglas K. Spracklin

  2. Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research & Development, 620 Memorial Drive, Cambridge, MA, 02139, USA

    Amit S. Kalgutkar

  3. Metabolism and Discovery Services, Unilabs York Bioanalytical Solutions, Discovery Park, Ramsgate Road, Sandwich, CT 13 9ND, UK

    Angus N. R. Nedderman

Authors
  1. Douglas K. Spracklin
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  2. Amit S. Kalgutkar
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  3. Angus N. R. Nedderman
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Correspondence to Douglas K. Spracklin .

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  1. Vertex Pharmaceuticals, Boston, Massachusetts, USA

    James R. Empfield

  2. Vertex Pharmaceuticals, Boston, Massachusetts, USA

    Michael P Clark

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Spracklin, D.K., Kalgutkar, A.S., Nedderman, A.N.R. (2013). The Role of Biotransformation Studies in Reducing Drug Attrition. In: Empfield, J., P Clark, M. (eds) Reducing Drug Attrition. Topics in Medicinal Chemistry, vol 11. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2012_18

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