Utility of human/human-derived reagents in drug discovery and development: An industrial perspective.

The shift to combinatorial chemistry and parallel synthesis in drug discovery has resulted in large numbers of compounds entering the lead seeking and lead development phases of the process. To support this, higher throughput computational (in silico) and in vitro approaches have become the forefront of the drug metabolism and pharmacokinetic (DMPK) input into drug discovery. This has been accompanied by a shift in focus from animal-derived data to human based studies, reflecting the realisation that extrapolation from animals to human has its limitations. In silico approaches may be regarded as human derived tools for DMPK, since models (template/pharmacophore and protein homology modelling), for example, for the human CYP enzymes, are widely used for identifying qualitatively enzyme/substrate interactions. Quantitative assessment of drug metabolism using human hepatocytes or sub-cellular fractions provide a valuable tool both for the screening out of high metabolic lability and in estimations of human intrinsic clearance. In terms of drug absorption, the human colon adenocarcinoma cell line, Caco-2, offers a versatile human derived system for measuring drug permeability, despite over expression of the efflux transporter P-glycoprotein (P-gp). The importance of P-gp can then be further assessed in recombinant systems expressing the human P-gp, where substrate affinity and inhibition potency can be measured, important factors when considering transporter mediated drug-drug interactions. The primary cause of pharmacokinetic-based drug-drug interactions (DDIs) is through enzyme inhibition or induction, with the CYP enzymes being of major importance. Human liver microsomes and hepatocytes are invaluable tools in assessment of DDI vulnerability of new chemical entities, having the capacity to identify enzymes responsible for specific routes of metabolism, and hence areas of vulnerability for a DDI. In addition, human-based screening tools can be used to identify the perpetrator of a DDI through enzyme inhibition/induction. Large differences in the nature of enzymes induced and the extent of induction when comparing animals to man are known. Thus, in vitro models allowing assessment of induction potential in human tissue, establishes some relevance to the clinical situation.