Rapid assessment of drug metabolism in the drug discovery process

For a few years, in vitro models have been used as part of high-throughput screening (HTS) programs to characterize metabolic stability, drug permeabi lity and drug solubility. This has allowed the rapid selection of lead cand idates based not only on pharmacological endpoints but also on biopharmaceu tical specifications. What has now become clear is that the huge amount of data produced to sort series of compounds has a limited predictive value wh en used to predict human pharmacokinetic parameters. More complex in vitro tests together with some simple in vivo tests used as validation steps have been developed in order to provide absolute data that may be used as a com plement to lead selection providing reliable predictions not only of human pharmacokinetics but also of potential drug-drug interactions. These models may be used as part of selective drug screening (SDS) programs. Further ad vances in analytical and in vitro techniques will see some of these models shifting from SDS to HTS programs putting the emphasis on the use of expert systems and physiologically based pharmacokinetic models (PBPK) to provide meaningful endpoint data. (C) 2000 Elsevier Science B.V. All rights reserv ed.