The Influence of DMPK as an Integrated Partner in Modern Drug Discovery

Robert J. Riley; Iain J. Martin; Anne E. Cooper

Abstract

In response to the challenge laid down by advances in other drug discovery functions, DMPK has now established an array of automated, miniaturised in vitro screens, rapid bioanalytical methodologies and in silico tools with which to optimise or predict passive absorption, metabolic clearance and minimise drug-drug interaction potential. The awareness of the pivotal role that physicochemical properties play in the control of many of these processes has been key. This review highlights some of these structure-activity relationships with emphasis on drug absorption, clearance, protein binding and distribution. However, some fundamental processes remain to be elucidated fully, including the in vivo impact of non-specific or futile binding in in vitro screens and the functional significance of intestinal and hepatobiliary transporter proteins. Transgenic animals should soon add value to our understanding of the contribution of transporter proteins to drug bioavailability (intestinal and hepatic drug uptake/efflux) and drug interactions and in validating projections for Man. Future studies should also focus on the evaluation of the various in vitro human CYP induction screens available, with particular emphasis on their predictive value for the clinical scenario.

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