High Throughput ADME Screening: Practical Considerations, Impact on the Portfolio and Enabler of In Silico ADME Models

Walter      Mitchell; Sabrina   X.   Zhao; Veronica      Zelesky; Kevin   M.   Whalen; Michael      West; John      Umland; Matt   D.   Troutman; Christine      Taylor; John   R.   Soglia; Stefan   J.   Steyn; Mark      Snyder; Cornelis   E.C.A.   Hop; Theodore   E.   Liston; Rebecca      Lebowitz; Suzanne      Krueger; Kelly      Jenkins; John   S.   Janiszewski; James      Federico; David   B.   Duignan; Ralph   E.   Davidson; Mark   J.   Cole

doi:10.2174/138920008786485092

Abstract

Evaluation and optimization of drug metabolism and pharmacokinetic data plays an important role in drug discovery and development and several reliable in vitro ADME models are available. Recently higher throughput in vitro ADME screening facilities have been established in order to be able to evaluate an appreciable fraction of synthesized compounds. The ADME screening process can be dissected in five distinct steps: (1) plate management of compounds in need of in vitro ADME data, (2) optimization of the MS/MS method for the compounds, (3) in vitro ADME experiments and sample clean up, (4) collection and reduction of the raw LC-MS/MS data and (5) archival of the processed ADME data. All steps will be described in detail and the value of the data on drug discovery projects will be discussed as well. Finally, in vitro ADME screening can generate large quantities of data obtained under identical conditions to allow building of reliable in silico models.

Keywords: Absorption, ADME, data management, in silico, in vitro, mass spectrometry, metabolism, pharmacokinetics