Discovery DMPK: changing paradigms in the eighties, nineties and noughties

Abstract

Background: The science of drug metabolism and pharmacokinetics (DMPK) plays a critical role in supporting the selection of potent, selective leads that retain the appropriate physicochemical properties to ensure distribution from the site of administration into the tissue or target of interest. Historically, Discovery DMPK has bridged the gap between the disciplines of biology and medicinal chemistry thereby ensuring a clinical focus during the discovery and early development phases. Objective: Here we discuss the fundamentals of DMPK screening in drug discovery from a historical perspective, highlighting DMPK's part in improving the chances of success for novel drug candidates and suggesting new and exciting areas for future development. Conclusions: Such a broad remit has resulted in the development of a wide variety of assays, both in vitro and in vivo, focused on assessing the developability risks associated with a molecule's progression into clinical development, such as likely bioavailability in humans, the potential for drug–drug interactions, human metabolism, interactions with transporters and the potential for metabolism-mediated idiosyncratic toxicity. Arguably DMPK has already adopted many of the concepts now of interest in translational medicine and quantitative pharmacology while scientific and regulatory pressures continue to drive the subject towards better and more integrated approaches, such as systems thinking.

Keywords::

• DMPK
• drug discovery
• PK/PD
• systems biology
• translational sciences

Acknowledgements

The authors are grateful for the many discussions within GlaxoSmithKline that have contributed to the thinking behind this manuscript. In particular, we acknowledge Andrew Ayrton for his feedback and also for crystallising the ideas described in Table 3.

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