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.